Imidazopyrazine syk inhibitors

ABSTRACT

Certain imidazopyrazines and pharmaceutical compositions thereof are provided herein. Methods of treating patients suffering from certain diseases and disorders responsive to the inhibition of Syk activity, which comprises administering to such patients an amount of at least one chemical entity effective to reduce signs or symptoms of the disease or disorder are provided. Also provided are methods for determining the presence or absence of Syk kinase in a sample.

This application claims the benefit of provisional U.S. PatentApplication No. 61/120,590, filed Dec. 8, 2008, provisional U.S. PatentApplication No. 61/140,535, filed Dec. 23, 2008, and provisional U.S.Patent Application No. 61/240,983, filed Sep. 9, 2009, each of which ishereby incorporated by reference.

Provided herein are certain imidazopyrazines, compositions, and methodsof their manufacture and use.

Protein kinases, the largest family of human enzymes, encompass wellover 500 proteins. Spleen Tyrosine Kinase (Syk) is a member of the Sykfamily of tyrosine kinases, and is a regulator of early B-celldevelopment as well as mature B-cell activation, signaling, andsurvival.

Syk is a non-receptor tyrosine kinase that plays critical roles inimmunoreceptor- and integrin-mediated signaling in a variety of celltypes, including B cells, macrophages, monocytes, mast cells,eosinophils, basophils, neutrophils, dendritic cells, T cells, naturalkiller cells, platelets, and osteoclasts. Immunoreceptors as describedhere include classical immunoreceptors and immunoreceptor-likemolecules. Classical immunoreceptors include B-cell and T-cell antigenreceptors as well as various immunoglobulin receptors (Fc receptors).Immunoreceptor-like molecules are either structurally related toimmunoreceptors or participate in similar signal transduction pathwaysand are primarily involved in non-adaptive immune functions, includingneutrophil activation, natural killer cell recognition, and osteoclastactivity. Integrins are cell surface receptors that play key roles inthe control of leukocyte adhesion and activation in both innate andadaptive immunity.

Ligand binding leads to activation of both immunoreceptors andintegrins, which results in Src family kinases being activated, andphosphorylation of immunoreceptor tyrosine-based activation motifs(ITAMs) in the cytoplasmic face of receptor-associated transmembraneadaptors. Syk binds to the phosphorylated ITAM motifs of the adaptors,leading to activation of Syk and subsequent phosphorylation andactivation of downstream signaling pathways.

Syk is essential for B-cell activation through B-cell receptor (BCR)signaling. SYK becomes activated upon binding to phosphoryated BCR andthus initiates the early signaling events following BCR activation.B-cell signaling through BCR can lead to a wide range of biologicaloutputs, which in turn depend on the developmental stage of the B-cell.The magnitude and duration of BCR signals must be precisely regulated.Aberrant BCR-mediated signaling can cause disregulated B-cell activationand/or the formation of pathogenic auto-antibodies leading to multipleautoimmune and/or inflammatory diseases. Mice lacking Syk show impairedmaturation of B-cells, diminished immunoglobulin production, compromisedT-cell-independent immune responses and marked attenuation of thesustained calcium sign upon BCR stimulation.

A large body of evidence supports the role of B-cells and the humoralimmune system in the pathogenesis of autoimmune and/or inflammatorydiseases. Protein-based therapeutics (such as Rituxan) developed todeplete B-cells represent an approach to the treatment of a number ofautoimmune and inflammatory diseases. Auto-antibodies and theirresulting immune complexes are known to play pathogenic roles inautoimmune disease and/or inflammatory disease. The pathogenic responseto these antibodies is dependent on signaling through Fc Receptors,which is, in turn, dependent upon Syk. Because of Syk's role in B-cellactivation, as well as FcR dependent signaling, inhibitors of Syk can beuseful as inhibitors of B-cell mediated pathogenic activity, includingautoantibody production. Therefore, inhibition of Syk enzymatic activityin cells is proposed as a treatment for autoimmune disease through itseffects on autoantibody production.

Syk also plays a key role in FCεRI mediated mast cell degranulation andeosinophil activation. Thus, Syk is implicated in allergic disordersincluding asthma. Syk binds to the phosphorylated gamma chain of FCεRIvia its SH2 domains and is essential for downstream signaling. Sykdeficient mast cells demonstrate defective degranulation, arachidonicacid and cytokine secretion. This also has been shown for pharmacologicagents that inhibit Syk activity in mast cells. Treatment with Sykantisense oligonucleotides inhibits antigen-induced infiltration ofeosinophils and neutrophils in an animal model of asthma. Syk deficienteosinophils also show impaired activation in response to FCεRIstimulation. Therefore, small molecule inhibitors of Syk will be usefulfor treatment of allergy-induced inflammatory diseases including asthma.

Syk is also expressed in mast cells and monocytes and has been shown tobe important for the function of these cells. For example, Sykdeficiency in mice is associated with impaired IgE-mediated mast cellactivation, which is marked diminution of TNF-alpha and otherinflammatory cytokine release. Syk kinase inhibitors have also beenshown to inhibit mast cell degranulation in cell based assays.Additionally, a Syk inhibitors have been shown to inhibitantigen-induced passive cutaneous anaphylaxsis, bronchoconstriction andbronchial edema in rats.

Thus, the inhibition of Syk activity can be useful for the treatment ofallergic disorders, autoimmune diseases and inflammatory diseases suchas: SLE, rheumatoid arthritis, multiple vasculitides, idiopathicthrombocytopenic purpura (ITP), myasthenia gravis, allergic rhinitis,chronic obstructive pulmonary disease (COPD), adult respiratory distresssyndrome (ARDS) and asthma. In addition, Syk has been reported to playan important role in ligand-independent tonic signaling through theB-cell receptor, known to be an important survival signal in B-cells.Thus, inhibition of Syk activity may be useful in treating certain typesof cancer, including B-cell lymphoma and leukemia.

Provided is at least one chemical entity chosen from compounds ofFormula I:

and pharmaceutically acceptable salts thereof, wherein

-   R₁ is pyridinyl, pyridazinyl, or pyrazolyl, each of which is    optionally substituted, or-   R₁ is

wherein A is an optionally substituted heteroaryl group having from 5 to7 ring atoms including the atoms shared with the 6 membered aromaticring;

-   R₂ is chosen from substituted aryl and optionally substituted    heteroaryl;-   R₃ is hydrogen;-   R₄ is hydrogen; and-   R₅ is hydrogen,-   provided that-   if R₁ is 2-methoxy-pyridin-5-yl, then R₂ is not 2,6-dimethylphenyl,    2-methoxyphenyl, 2-chlorophenyl, or 2-fluorophenyl;-   if R₁ is indol-5-yl, then R₂ is not 2-chlorophenyl, furan-2-yl, or    3-chloro-4-fluorophenyl;-   if R₁ is 1H-indazol-5-yl, 1H-indol-6-yl, benzo[d]oxazole-6-yl,    benzo[d]isoxazole-6-yl, benzothiazol-6-yl, or 3H-benzoimidazol-5-yl,    then R₂ is not 3-aminophenyl; and-   if R₁ is 1H-indazol-6-yl, then R₂ is not 3-carboxyphenyl or    4-carboxyphenyl.

Also provided is a pharmaceutical composition, comprising at least onechemical entity described herein, together with at least onepharmaceutically acceptable vehicle chosen from carriers, adjuvants, andexcipients.

Also provided is a method for treating a patient having a diseaseresponsive to inhibition of Syk activity, comprising administering tothe patient an effective amount of at least one chemical entitydescribed herein.

Also provided is a method for treating a patient having a disease chosenfrom cancer, autoimmune diseases, inflammatory diseases, acuteinflammatory reactions, and allergic disorders comprising administeringto the patient an effective amount of at least one chemical entitydescribed herein. Also provided is a method for treating a patienthaving polycystic kidney disease comprising administering to the patientan effective amount of at least one chemical entity described herein.

Also provided is a method for increasing sensitivity of cancer cells tochemotherapy, comprising administering to a patient undergoingchemotherapy with a chemotherapeutic agent an amount of at least onechemical entity described herein, sufficient to increase the sensitivityof cancer cells to the chemotherapeutic agent.

Also provided is a method for inhibiting ATP hydrolysis, the methodcomprising contacting cells expressing Syk with at least one chemicalentity described herein in an amount sufficient to detectably decreasethe level of ATP hydrolysis in vitro.

Also provided is a method for determining the presence of Syk in asample, comprising contacting the sample with at least one chemicalentity described herein under conditions that permit detection of Sykactivity, detecting a level of Syk activity in the sample, and therefromdetermining the presence or absence of Syk in the sample.

Also provided is a method for inhibiting B-cell activity comprisingcontacting cells expressing Syk with at least one chemical entitydescribed herein in an amount sufficient to detectably decrease B-cellactivity in vitro.

As used herein, when any variable occurs more than one time in achemical formula, its definition on each occurrence is independent ofits definition at every other occurrence. In accordance with the usualmeaning of “a” and “the” in patents, reference, for example, to “a”kinase or “the” kinase is inclusive of one or more kinases.

As used in the present specification, the following words, phrases andsymbols are generally intended to have the meanings as set forth below,except to the extent that the context in which they are used indicatesotherwise. The following abbreviations and terms have the indicatedmeanings throughout:

A dash (“-”) that is not between two letters or symbols is used toindicate a point of attachment for a substituent. For example, —CONH₂ isattached through the carbon atom.

By “optional” or “optionally” is meant that the subsequently describedevent or circumstance may or may not occur, and that the descriptionincludes instances where the event or circumstance occurs and instancesin which it does not. For example, “optionally substituted alkyl”encompasses both “alkyl” and “substituted alkyl” as defined below. Itwill be understood by those skilled in the art, with respect to anygroup containing one or more substituents, that such groups are notintended to introduce any substitution or substitution patterns that aresterically impractical, synthetically non-feasible and/or inherentlyunstable.

“Alkyl” encompasses straight chain and branched chain having theindicated number of carbon atoms, usually from 1 to 20 carbon atoms, forexample 1 to 8 carbon atoms, such as 1 to 6 carbon atoms. For exampleC₁-C₆ alkyl encompasses both straight and branched chain alkyl of from 1to 6 carbon atoms. Examples of alkyl groups include methyl, ethyl,propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl,isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, 3-methylpentyl, and thelike. Alkylene is another subset of alkyl, referring to the sameresidues as alkyl, but having two points of attachment. Alkylene groupswill usually have from 2 to 20 carbon atoms, for example 2 to 8 carbonatoms, such as from 2 to 6 carbon atoms. For example, C₀ alkyleneindicates a covalent bond and C₁ alkylene is a methylene group. When analkyl residue having a specific number of carbons is named, allgeometric isomers having that number of carbons are intended to beencompassed; thus, for example, “butyl” is meant to include n-butyl,sec-butyl, isobutyl and t-butyl; “propyl” includes n-propyl andisopropyl. “Lower alkyl” refers to alkyl groups having 1 to 4 carbons.

“Alkenyl” indicates an unsaturated branched or straight-chain alkylgroup having at least one carbon-carbon double bond derived by theremoval of one molecule of hydrogen from adjacent carbon atoms of theparent alkyl. The group may be in either the cis or trans configurationabout the double bond(s). Typical alkenyl groups include, but are notlimited to, ethenyl; propenyls such as prop-1-en-1-yl, prop-1-en-2-yl,prop-2-en-1-yl(allyl), prop-2-en-2-yl; butenyls such as but-1-en-1-yl,but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl, but-2-en-1-yl,but-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl; and the like. Insome embodiments, an alkenyl group has from 2 to 20 carbon atoms and inother embodiments, from 2 to 6 carbon atoms.

“Cycloalkyl” indicates a saturated hydrocarbon ring group, having thespecified number of carbon atoms, usually from 3 to 7 ring carbon atoms.Examples of cycloalkyl groups include cyclopropyl, cyclobutyl,cyclopentyl, and cyclohexyl as well as bridged and caged saturated ringgroups such as norbornane.

By “alkoxy” is meant an alkyl group of the indicated number of carbonatoms attached through an oxygen bridge such as, for example, methoxy,ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentoxy,2-pentyloxy, isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy,3-methylpentoxy, and the like. Alkoxy groups will usually have from 1 to6 carbon atoms attached through the oxygen bridge. “Lower alkoxy” refersto alkoxy groups having 1 to 4 carbons.

“Aminocarbonyl” encompasses a group of the formula —(C═O)NR_(a)R_(b)where R_(a) and R_(b) are independently chosen from hydrogen and theoptional substituents for “substituted amino” described below.

“Acyl” refers to the groups (alkyl)-C(O)—; (cycloalkyl)-C(O)—;(aryl)-C(O)—; (heteroaryl)-C(O)—; and (heterocycloalkyl)-C(O)—, whereinthe group is attached to the parent structure through the carbonylfunctionality and wherein alkyl, cycloalkyl, aryl, heteroaryl, andheterocycloalkyl are as described herein. Acyl groups have the indicatednumber of carbon atoms, with the carbon of the keto group being includedin the numbered carbon atoms. For example a C₂ acyl group is an acetylgroup having the formula CH₃(C═O)—.

By “alkoxycarbonyl” is meant an ester group of the formula(alkoxy)(C═O)— attached through the carbonyl carbon wherein the alkoxygroup has the indicated number of carbon atoms. Thus aC₁-C₆alkoxycarbonyl group is an alkoxy group having from 1 to 6 carbonatoms attached through its oxygen to a carbonyl linker.

By “amino” is meant the group —NH₂.

“Aryl” encompasses:

-   -   5- and 6-membered carbocyclic aromatic rings, for example,        benzene;    -   bicyclic ring systems wherein at least one ring is carbocyclic        and aromatic, for example, naphthalene, indane, and tetralin;        and    -   tricyclic ring systems wherein at least one ring is carbocyclic        and aromatic, for example, fluorene.        For example, aryl includes 5- and 6-membered carbocyclic        aromatic rings fused to a 5- to 7-membered heterocycloalkyl ring        containing 1 or more heteroatoms chosen from N, O, and S. For        such fused, bicyclic ring systems wherein only one of the rings        is a carbocyclic aromatic ring, the point of attachment may be        at the carbocyclic aromatic ring or the heterocycloalkyl ring.        Bivalent radicals formed from substituted benzene derivatives        and having the free valences at ring atoms are named as        substituted phenylene radicals. Bivalent radicals derived from        univalent polycyclic hydrocarbon radicals whose names end in        “-yl” by removal of one hydrogen atom from the carbon atom with        the free valence are named by adding “-idene” to the name of the        corresponding univalent radical, e.g., a naphthyl group with two        points of attachment is termed naphthylidene. Aryl, however,        does not encompass or overlap in any way with heteroaryl,        separately defined below. Hence, if one or more carbocyclic        aromatic rings is fused with a heterocycloalkyl aromatic ring,        the resulting ring system is heteroaryl, not aryl, as defined        herein.

The term “aryloxy” refers to the group —O-aryl.

The term “halo” includes fluoro, chloro, bromo, and iodo, and the term“halogen” includes fluorine, chlorine, bromine, and iodine.

“Heteroaryl” encompasses:

-   -   5- to 7-membered aromatic, monocyclic rings containing one or        more, for example, from 1 to 4, or In some embodiments, from 1        to 3, heteroatoms chosen from N, O, and S, with the remaining        ring atoms being carbon; and    -   bicyclic heterocycloalkyl rings containing one or more, for        example, from 1 to 4, or In some embodiments, from 1 to 3,        heteroatoms chosen from N, O, and S, with the remaining ring        atoms being carbon and wherein at least one heteroatom is        present in an aromatic ring.        For example, heteroaryl includes a 5- to 7-membered        heterocycloalkyl, aromatic ring fused to a 5- to 7-membered        cycloalkyl ring. For such fused, bicyclic heteroaryl ring        systems wherein only one of the rings contains one or more        heteroatoms, the point of attachment may be at the        heteroaromatic ring or the cycloalkyl ring. When the total        number of S and O atoms in the heteroaryl group exceeds 1, those        heteroatoms are not adjacent to one another. In some        embodiments, the total number of S and O atoms in the heteroaryl        group is not more than 2. In some embodiments, the total number        of S and O atoms in the aromatic heterocycle is not more than 1.        Examples of heteroaryl groups include, but are not limited to,        (as numbered from the linkage position assigned priority 1),        2-pyridyl, 3-pyridyl, 4-pyridyl, 2,3-pyrazinyl, 3,4-pyrazinyl,        2,4-pyrimidinyl, 3,5-pyrimidinyl, 2,3-pyrazolinyl,        2,4-imidazolinyl, isoxazolinyl, oxazolinyl, thiazolinyl,        thiadiazolinyl, tetrazolyl, thienyl, benzothiophenyl, furanyl,        benzofuranyl, benzoimidazolinyl, indolinyl, pyridizinyl,        triazolyl, quinolinyl, pyrazolyl, and        5,6,7,8-tetrahydroisoquinoline. Bivalent radicals derived from        univalent heteroaryl radicals whose names end in “-yl” by        removal of one hydrogen atom from the atom with the free valence        are named by adding “-idene” to the name of the corresponding        univalent radical, e.g., a pyridyl group with two points of        attachment is a pyridylidene. Heteroaryl does not encompass or        overlap with aryl as defined above.

Substituted heteroaryl also includes ring systems substituted with oneor more oxide (—O⁻) substituents, such as pyridinyl N-oxides.

The term “heteroaryloxy” refers to the group —O-heteroaryl.

By “heterocycloalkyl” is meant a single aliphatic ring, usually with 3to 7 ring atoms, containing at least 2 carbon atoms in addition to 1-3heteroatoms independently selected from oxygen, sulfur, and nitrogen, aswell as combinations comprising at least one of the foregoingheteroatoms. Suitable heterocycloalkyl groups include, for example (asnumbered from the linkage position assigned priority 1), 2-pyrrolinyl,2,4-imidazolidinyl, 2,3-pyrazolidinyl, 2-piperidyl, 3-piperidyl,4-piperdyl, and 2,5-piperzinyl. Morpholinyl groups are alsocontemplated, including 2-morpholinyl and 3-morpholinyl (numberedwherein the oxygen is assigned priority 1). Substituted heterocycloalkylalso includes ring systems substituted with one or more oxo moieties,such as piperidinyl N-oxide, morpholinyl-N-oxide,1-oxo-1-thiomorpholinyl and 1,1-dioxo-1-thiomorpholinyl.

The term “heterocycloalkyloxy” refers to the group —O-heterocylcoalkyl.

The term “nitro” refers to the group —NO₂.

The term “phosphono” refers to the group —PO₃H₂.

“Thiocarbonyl” refers to the group —C(═O)SH.

The term “optionally substituted thiocarbonyl” includes the followinggroups: —C(═O)S-(optionally substituted (C₁-C₆)alkyl),—C(═O)S-(optionally substituted aryl), —C(═O)S-(optionally substitutedheteroaryl), and —C(═O)S-(optionally substituted heterocycloalkyl).

The term “sulfanyl” includes the groups: —S-(optionally substituted(C₁-C₆)alkyl), —S-(optionally substituted aryl), —S-(optionallysubstituted heteroaryl), and —S-(optionally substitutedheterocycloalkyl). Hence, sulfanyl includes the group C₁-C₆alkylsulfanyl.

The term “sulfinyl” includes the groups: —S(O)—H, —S(O)-(optionallysubstituted (C₁-C₆)alkyl), —S(O)-optionally substituted aryl),—S(O)-optionally substituted heteroaryl), —S(O)-(optionally substitutedheterocycloalkyl); and —S(O)-(optionally substituted amino).

The term “sulfonyl” includes the groups: —S(O₂)—H, —S(O₂)-(optionallysubstituted (C₁-C₆)alkyl), —S(O₂)-optionally substituted aryl),—S(O₂)-optionally substituted heteroaryl), —S(O₂)-(optionallysubstituted heterocycloalkyl), —S(O₂)-(optionally substituted alkoxy),—S(O₂)-optionally substituted aryloxy), —S(O₂)-optionally substitutedheteroaryloxy), —S(O₂)-(optionally substituted heterocyclyloxy); and—S(O₂)-(optionally substituted amino).

The term “substituted”, as used herein, means that any one or morehydrogens on the designated atom or group is replaced with a selectionfrom the indicated group, provided that the designated atom's normalvalence is not exceeded. When a substituent is oxo (i.e., ═O) then 2hydrogens on the atom are replaced. Combinations of substituents and/orvariables are permissible only if such combinations result in stablecompounds or useful synthetic intermediates. A stable compound or stablestructure is meant to imply a compound that is sufficiently robust tosurvive isolation from a reaction mixture, and subsequent formulation asan agent having at least practical utility. Unless otherwise specified,substituents are named into the core structure. For example, it is to beunderstood that when (cycloalkyl)alkyl is listed as a possiblesubstituent, the point of attachment of this substituent to the corestructure is in the alkyl portion.

The terms “substituted” alkyl, cycloalkyl, aryl, heterocycloalkyl, andheteroaryl (including without limitation pyridinyl, pyridazinyl,pyrazolyl, oxazolyl, pyrrolyl, thiazolyl, and imidazolyl group), unlessotherwise expressly defined, refer respectively to alkyl, cycloalkyl,aryl, heterocycloalkyl, and heteroaryl (including without limitationpyridinyl, pyridazinyl, pyrazolyl, oxazolyl, pyrrolyl, thiazolyl, andimidazolyl group) wherein one or more (such as up to 5, for example, upto 3) hydrogen atoms are replaced by a substituent independently chosenfrom:

—R^(a), —OR^(b), —O(C₁-C₂ alkyl)O— (e.g., methylenedioxy-), —SR^(b),guanidine, guanidine wherein one or more of the guanidine hydrogens arereplaced with a lower-alkyl group, —NR^(b)R^(c), halo, cyano, oxo (as asubstituent for heterocycloalkyl), nitro, —COR^(b), —CO₂R^(b),—CONR^(b)R^(c), —OCOR^(b), —OCO₂R^(a), —OCONR^(b)R^(c), —NR^(c)COR^(b),—NR^(c)CO₂R^(a), —NR^(c)CONR^(b)R^(c), —SOR^(a), —SO₂R^(a),—SO₂NR^(b)R^(c), and —NR^(c)SO₂R^(a),

where R^(a) is chosen from optionally substituted C₁-C₆ alkyl,optionally substituted cycloalkyl, optionally substituted aryl,optionally substituted heterocycloalkyl, and optionally substitutedheteroaryl;

R^(b) is chosen from H, optionally substituted C₁-C₆ alkyl, optionallysubstituted aryl, and optionally substituted heteroaryl; and

R^(c) is chosen from hydrogen and optionally substituted C₁-C₄ alkyl; or

R^(b) and R^(c), and the nitrogen to which they are attached, form anoptionally substituted heterocycloalkyl group; and

where each optionally substituted group is unsubstituted orindependently substituted with one or more, such as one, two, or three,substituents independently selected from C₁-C₄ alkyl, C₃-C₆ cycloalkyl,aryl, heteroaryl, aryl-C₁-C₄ alkyl-, heteroaryl-C₁-C₄ alkyl-, C₁-C₄haloalkyl-, —OC₁-C₄ alkyl, —OC₁-C₄ alkylphenyl, —C₁-C₄ alkyl-OH, —C₁-C₄alkyl-O—C₁-C₄ alkyl, —OC₁-C₄ haloalkyl, halo, —OH, —NH₂, —C₁-C₄alkyl-NH₂, —N(C₁-C₄ alkyl)(C₁-C₄ alkyl), —NH(C₁-C₄ alkyl), —N(C₁-C₄alkyl)(C₁-C₄ alkylphenyl), —NH(C₁-C₄ alkylphenyl), cyano, nitro, oxo (asa substitutent for heteroaryl), —CO₂H, —C(O)OC₁-C₄ alkyl, —CON(C₁-C₄alkyl)(C₁-C₄ alkyl), —CONH(C₁-C₄ alkyl), —CONH₂, —NHC(O)(C₁-C₄ alkyl),—NHC(O)(phenyl), —N(C₁-C₄ alkyl)C(O)(C₁-C₄ alkyl), —N(C₁-C₄alkyl)C(O)(phenyl), —C(O)C₁-C₄ alkyl, —C(O)C₁-C₄ phenyl, —C(O)C₁-C₄haloalkyl, —OC(O)C₁-C₄ alkyl, —SO₂(C₁-C₄ alkyl), —SO₂(phenyl),—SO₂(C₁-C₄ haloalkyl), —SO₂NH₂, —SO₂NH(C₁-C₄ alkyl), —SO₂NH(phenyl),—NHSO₂(C₁-C₄ alkyl), —NHSO₂(phenyl), and —NHSO₂(C₁-C₄ haloalkyl).

The term “substituted acyl” refers to the groups (substitutedalkyl)-C(O)—; (substituted cycloalkyl)-C(O)—; (substituted aryl)-C(O)—;(substituted heteroaryl)-C(O)—; and (substitutedheterocycloalkyl)-C(O)—, wherein the group is attached to the parentstructure through the carbonyl functionality and wherein substitutedalkyl, cycloalkyl, aryl, heteroaryl, and heterocycloalkyl are asdescribed herein.

The term “substituted alkoxy” refers to alkoxy wherein the alkylconstituent is substituted (i.e., —O-(substituted alkyl)) wherein“substituted alkyl” is as described herein.

The term “substituted alkoxycarbonyl” refers to the group (substitutedalkyl)-O—C(O)— wherein the group is attached to the parent structurethrough the carbonyl functionality and wherein substituted alkyl is asdescribed herein.

The term “substituted aryloxy” refers to aryloxy wherein the arylconstituent is substituted (i.e., —O-(substituted aryl)) wherein“substituted aryl” is as described herein.

The term “substituted heteroaryloxy” refers to heteroaryloxy wherein thearyl constituent is substituted (i.e., —O-(substituted heteroaryl))wherein “substituted heteroaryl” is as described herein.

The term “substituted cycloalkyloxy” refers to cycloalkyloxy wherein thecycloalkyl constituent is substituted (i.e., —O-(substitutedcycloalkyl)) wherein “substituted cycloalkyl” is as described herein.

The term “substituted heterocycloalkyloxy” refers to heterocycloalkyloxywherein the alkyl constituent is substituted (i.e., —O-(substitutedheterocycloalkyl)) wherein “substituted heterocycloalkyl” is asdescribed herein.

The term “substituted amino” refers to the group —NHR^(d) or—NR^(d)R^(d) where each R^(d) is independently chosen from: hydroxy,optionally substituted alkyl, optionally substituted cycloalkyl,optionally substituted acyl, aminocarbonyl, optionally substituted aryl,optionally substituted heteroaryl, optionally substitutedheterocycloalkyl, alkoxycarbonyl, sulfinyl and sulfonyl, each asdescribed herein, and provided that only one R^(d) may be hydroxyl. Theterm “substituted amino” also refers to N-oxides of the groups —NHR^(d),and NR^(d)R^(d) each as described above. N-oxides can be prepared bytreatment of the corresponding amino group with, for example, hydrogenperoxide or m-chloroperoxybenzoic acid. The person skilled in the art isfamiliar with reaction conditions for carrying out the N-oxidation.

Compounds described herein include, but are not limited to, theiroptical isomers, racemates, and other mixtures thereof. In thosesituations, the single enantiomers or diastereomers, i.e., opticallyactive forms, can be obtained by asymmetric synthesis or by resolutionof the racemates. Resolution of the racemates can be accomplished, forexample, by conventional methods such as crystallization in the presenceof a resolving agent, or chromatography, using, for example a chiralhigh-pressure liquid chromatography (HPLC) column. In addition, suchcompounds include Z- and E-forms (or cis- and trans-forms) of compoundswith carbon-carbon double bonds. Where compounds described herein existin various tautomeric forms, chemical entities include all tautomericforms of the compound. Such compounds also include crystal formsincluding polymorphs and clathrates.

Compounds of Formula I also include crystalline and amorphous forms ofthose compounds, including, for example, polymorphs, pseudopolymorphs,solvates, hydrates, unsolvated polymorphs (including anhydrates),conformational polymorphs, and amorphous forms of the compounds, as wellas mixtures thereof. “Crystalline form,” “polymorph,” and “novel form”may be used interchangeably herein, and are meant to include allcrystalline and amorphous forms of the compound, including, for example,polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs(including anhydrates), conformational polymorphs, and amorphous forms,as well as mixtures thereof, unless a particular crystalline oramorphous form is referred to. Compounds of Formula I also includepharmaceutically acceptable forms of the recited compounds, includingchelates, non-covalent complexes, prodrugs, and mixtures thereof.

Compounds of Formula I also include different enriched isotopic forms,e.g., compounds enriched in the content of ²H, ³H, ¹¹C, ¹³C and/or ¹⁴C.In some embodiments, the compounds are deuterated. Such deuterated formscan be made by the procedure described in U.S. Pat. Nos. 5,846,514 and6,334,997. As described in U.S. Pat. Nos. 5,846,514 and 6,334,997,deuteration may improve the efficacy and increase the duration of actionof drugs.

Deuterium substituted compounds can be synthesized using various methodssuch as described in: Dean, Dennis C.; Editor. Recent Advances in theSynthesis and Applications of Radiolabeled Compounds for Drug Discoveryand Development. [In: Curr., Pharm. Des., 2000; 6(10)] 2000, 110 pp. CAN133:68895 AN 2000:473538 CAPLUS; Kabalka, George W.; Varma, Rajender S.The Synthesis of Radiolabeled Compounds via OrganometallicIntermediates, Tetrahedron, 1989, 45(21), 6601-21, CODEN: TETRAB ISSN:0040-4020. CAN 112:20527 AN 1990:20527 CAPLUS; and Evans, E. Anthony.Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2),9-32. CODEN: JRACBN ISSN: 0022-4081, CAN 95:76229 AN 1981:476229 CAPLUS.

Chemical entities include, but are not limited to compounds describedherein and all pharmaceutically acceptable forms thereof. Hence, theterms “chemical entity” and “chemical entities” also encompasspharmaceutically acceptable salts.

“Pharmaceutically acceptable salts” include, but are not limited tosalts with inorganic acids, such as hydrochlorate, phosphate,diphosphate, hydrobromate, sulfate, sulfinate, nitrate, and like salts;as well as salts with an organic acid, such as malate, maleate,fumarate, tartrate, succinate, citrate, acetate, lactate,methanesulfonate, p-toluenesulfonate, 2-hydroxyethylsulfonate, benzoate,salicylate, stearate, and alkanoate such as acetate, HOOC—(CH₂)_(n)—COOHwhere n is 0-4, and like salts. Similarly, pharmaceutically acceptablecations include, but are not limited to sodium, potassium, calcium,aluminum, lithium, and ammonium.

In addition, if the compounds described herein are obtained as an acidaddition salt, the free base can be obtained by basifying a solution ofthe acid salt. Conversely, if the product is a free base, an additionsalt, particularly a pharmaceutically acceptable addition salt, may beproduced by dissolving the free base in a suitable organic solvent andtreating the solution with an acid, in accordance with conventionalprocedures for preparing acid addition salts from base compounds. Thoseskilled in the art will recognize various synthetic methodologies thatmay be used to prepare non-toxic pharmaceutically acceptable additionsalts.

As noted above, prodrugs also fall within the scope of compounds ofFormula I. In some embodiments, the “prodrugs” described herein includeany compound that becomes a compound of Formula I when administered to apatient, e.g., upon metabolic processing of the prodrug. Examples ofprodrugs include derivatives of functional groups, such as a carboxylicacid group, in the compounds of Formula I. Exemplary prodrugs of acarboxylic acid group include, but are not limited to, carboxylic acidesters such as alkyl esters, hydroxyalkyl esters, arylalkyl esters, andaryloxyalkyl esters.

A “solvate” is formed by the interaction of a solvent and a compound.The term “compound” is intended to include solvates of compounds.Similarly, “salts” includes solvates of salts. Suitable solvates arepharmaceutically acceptable solvates, such as hydrates, includingmonohydrates and hemi-hydrates.

A “chelate” is formed by the coordination of a compound to a metal ionat two (or more) points. The term “compound” is intended to includechelates of compounds. Similarly, “salts” includes chelates of salts.

A “non-covalent complex” is formed by the interaction of a compound andanother molecule wherein a covalent bond is not formed between thecompound and the molecule. For example, complexation can occur throughvan der Waals interactions, hydrogen bonding, and electrostaticinteractions (also called ionic bonding). Such non-covalent complexesare included in the term “compound’.

The term “hydrogen bond” refers to a form of association between anelectronegative atom (also known as a hydrogen bond acceptor) and ahydrogen atom attached to a second, relatively electronegative atom(also known as a hydrogen bond donor). Suitable hydrogen bond donor andacceptors are well understood in medicinal chemistry (G. C. Pimentel andA. L. McClellan, The Hydrogen Bond, Freeman, San Francisco, 1960; R.Taylor and O. Kennard, “Hydrogen Bond Geometry in Organic Crystals”,Accounts of Chemical Research, 17, pp. 320-326 (1984)).

“Hydrogen bond acceptor” refers to a group comprising an oxygen ornitrogen, especially an oxygen or nitrogen that is sp²-hybridized, anether oxygen, or the oxygen of a sulfoxide or N-oxide.

The term “hydrogen bond donor” refers to an oxygen, nitrogen, orheteroaromatic carbon that bears a hydrogen group containing a ringnitrogen or a heteroaryl group containing a ring nitrogen.

As used herein the terms “group”, “radical” or “fragment” are synonymousand are intended to indicate functional groups or fragments of moleculesattachable to a bond or other fragments of molecules.

The term “active agent” is used to indicate a chemical entity which hasbiological activity. In some embodiments, an “active agent” is acompound having pharmaceutical utility. For example an active agent maybe an anti-cancer therapeutic.

The term “therapeutically effective amount” of a chemical entitydescribed herein means an amount effective, when administered to a humanor non-human patient, to provide a therapeutic benefit such asamelioration of symptoms, slowing of disease progression, or preventionof disease e.g., a therapeutically effective amount may be an amountsufficient to decrease the symptoms of a disease responsive toinhibition of Syk activity. In some embodiments, a therapeuticallyeffective amount is an amount sufficient to reduce cancer symptoms, thesymptoms of an allergic disorder, the symptoms of an autoimmune and/orinflammatory disease, or the symptoms of an acute inflammatory reaction.In some embodiments a therapeutically effective amount is an amountsufficient to decrease the number of detectable cancerous cells in anorganism, detectably slow, or stop the growth of a cancerous tumor. Insome embodiments, a therapeutically effective amount is an amountsufficient to shrink a cancerous tumor. In some embodiments, a patientsuffering from cancer may not present symptoms of being affected. Insome embodiments, a therapeutically effective amount of a chemicalentity is an amount sufficient to prevent a significant increase orsignificantly reduce the detectable level of cancerous cells or cancermarkers in the patient's blood, serum, or tissues. In some embodiments,a therapeutically effective amount may also be an amount sufficient,when administered to a patient, to detectably slow progression of thedisease, or prevent the patient to whom the chemical entity is givenfrom presenting symptoms of the allergic disorders and/or autoimmuneand/or inflammatory disease, and/or acute inflammatory response. In someembodiments, a therapeutically effective amount may also be an amountsufficient to produce a detectable decrease in the amount of a markerprotein or cell type in the patient's blood or serum. In someembodiments a therapeutically effective amount is an amount of achemical entity described herein sufficient to significantly decreasethe activity of B-cells. In some embodiments, a therapeuticallyeffective amount is an amount of a chemical entity described hereinsufficient to significantly decrease the number of B-cells. In someembodiments, a therapeutically effective amount is an amount of achemical entity described herein sufficient to decrease the level ofanti-acetylcholine receptor antibody in a patient's blood with thedisease myasthenia gravis.

The term “inhibition” indicates a significant decrease in the baselineactivity of a biological activity or process. “Inhibition of Sykactivity” refers to a decrease in Syk activity as a direct or indirectresponse to the presence of at least one chemical entity describedherein, relative to the activity of Syk in the absence of the at leastone chemical entity. The decrease in activity may be due to the directinteraction of the compound with Syk, or due to the interaction of thechemical entity(ies) described herein with one or more other factorsthat in turn affect Syk activity. For example, the presence of thechemical entity(ies) may decrease Syk activity by directly binding tothe Syk, by causing (directly or indirectly) another factor to decreaseSyk activity, or by (directly or indirectly) decreasing the amount ofSyk present in the cell or organism.

Inhibition of Syk activity also refers to observable inhibition of Sykactivity in a standard biochemical assay for Syk activity, such as theATP hydrolysis assay described below. In some embodiments, the chemicalentity described herein has an IC₅₀ value less than or equal to 1micromolar. In some embodiments, the chemical entity has an IC₅₀ valueless than or equal to less than 100 nanomolar. In some embodiments, thechemical entity has an IC₅₀ value less than or equal to 10 nanomolar.

“Inhibition of B-cell activity” refers to a decrease in B-cell activityas a direct or indirect response to the presence of at least onechemical entity described herein, relative to the activity of B-cells inthe absence of the at least one chemical entity. The decrease inactivity may be due to the direct interaction of the compound with Sykor with one or more other factors that in turn affect B-cell activity.

Inhibition of B-cell activity also refers to observable inhibition ofCD86 expression in a standard assay such as the assay described below.In some embodiments, the chemical entity described herein has an IC₅₀value less than or equal to 10 micromolar. In some embodiments, thechemical entity has an IC₅₀ value less than or equal to less than 1micromolar. In some embodiments, the chemical entity has an IC₅₀ valueless than or equal to 500 nanomolar.

“B cell activity” also includes activation, redistribution,reorganization, or capping of one or more various B cell membranereceptors, or membrane-bound immunoglobulins, e.g, IgM, IgG, and IgD.Most B cells also have membrane receptors for Fc portion of IgG in theform of either antigen-antibody complexes or aggregated IgG. B cellsalso carry membrane receptors for the activated components ofcomplement, e.g., C3b, C3d, C4, and Clq. These various membranereceptors and membrane-bound immunoglobulins have membrane mobility andcan undergo redistribution and capping that can initiate signaltransduction.

B cell activity also includes the synthesis or production of antibodiesor immunoglobulins. Immunoglobulins are synthesized by the B cell seriesand have common structural features and structural units. Fiveimmunoglobulin classes, i.e., IgG, IgA, IgM, IgD, and IgE, arerecognized on the basis of structural differences of their heavy chainsincluding the amino acid sequence and length of the polypeptide chain.Antibodies to a given antigen may be detected in all or several classesof immunoglobulins or may be restricted to a single class or subclass ofimmunoglobulin. Autoantibodies or autoimmune antibodies may likewisebelong to one or several classes of immunoglobulins. For example,rheumatoid factors (antibodies to IgG) are most often recognized as anIgM immunoglobulin, but can also consist of IgG or IgA.

In addition, B cell activity also is intended to include a series ofevents leading to B cell clonal expansion (proliferation) from precursorB lymphocytes and differentiation into antibody-synthesizing plasmacells which takes place in conjunction with antigen-binding and withcytokine signals from other cells.

“Inhibition of B-cell proliferation” refers to inhibition ofproliferation of abnormal B-cells, such as cancerous B-cells, e.g.lymphoma B-cells and/or inhibition of normal, non-diseased B-cells. Theterm “inhibition of B-cell proliferation” indicates any significantdecrease in the number of B-cells, either in vitro or in vivo. Thus aninhibition of B-cell proliferation in vitro would be any significantdecrease in the number of B-cells in an in vitro sample contacted withat least one chemical entity described herein as compared to a matchedsample not contacted with the chemical entity(ies).

Inhibition of B-cell proliferation also refers to observable inhibitionof B-cell proliferation in a standard thymidine incorporation assay forB-cell proliferation, such as the assay described herein. In someembodiments, the chemical entity has an IC₅₀ value less than or equal to10 micromolar. In some embodiments, the chemical entity has an IC₅₀value less than or equal to less than 1 micromolar. In some embodiments,the chemical entity has an IC₅₀ value less than or equal to 500nanomolar.

An “allergy” or “allergic disorder” refers to acquired hypersensitivityto a substance (allergen). Allergic conditions include eczema, allergicrhinitis or coryza, hay fever, bronchial asthma, urticaria (hives) andfood allergies, and other atopic conditions.

“Asthma” refers to a disorder of the respiratory system characterized byinflammation, narrowing of the airways and increased reactivity of theairways to inhaled agents. Asthma is frequently, although notexclusively associated with atopic or allergic symptoms.

By “significant” is meant any detectable change that is statisticallysignificant in a standard parametric test of statistical significancesuch as Student's T-test, where p<0.05.

A “disease responsive to inhibition of Syk activity” is a disease inwhich inhibiting Syk kinase provides a therapeutic benefit such as anamelioration of symptoms, decrease in disease progression, prevention ordelay of disease onset, or inhibition of aberrant activity of certaincell-types (monocytes, B-cells, and mast cells).

“Treatment or treating means any treatment of a disease in a patient,including:

-   -   a) preventing the disease, that is, causing the clinical        symptoms of the disease not to develop;    -   b) inhibiting the disease;    -   c) slowing or arresting the development of clinical symptoms;        and/or    -   d) relieving the disease, that is, causing the regression of        clinical symptoms.

“Patient” refers to an animal, such as a mammal, that has been or willbe the object of treatment, observation or experiment. The methodsdescribed herein may be useful in both human therapy and veterinaryapplications. In some embodiments, the patient is a mammal; in someembodiments the patient is human; and in some embodiments the patient ischosen from cats and dogs.

Provided is at least one chemical entity chosen from compounds ofFormula I:

and pharmaceutically acceptable salts thereof, wherein

-   R₁ is pyridinyl, pyridazinyl, or pyrazolyl, each of which is    optionally substituted, or-   R₁ is

wherein A is an optionally substituted heteroaryl group having from 5 to7 ring atoms including the atoms shared with the 6 membered aromaticring;

-   R₂ is chosen from substituted aryl and optionally substituted    heteroaryl;-   R₃ is hydrogen;-   R₄ is hydrogen; and-   R₅ is hydrogen,    provided that-   if R₁ is 2-methoxy-pyridin-5-yl, then R₂ is not 2,6-dimethylphenyl,    2-methoxyphenyl, 2-chlorophenyl, or 2-fluorophenyl;-   if R₁ is indol-5-yl, then R₂₂-chlorophenyl, furan-2-yl, or    3-chloro-4-fluorophenyl;-   if R₁ is 1H-indazol-5-yl, 1H-indol-6-yl, benzo[d]oxazole-6-yl,    benzo[d]isoxazole-6-yl, benzothiazol-6-yl, or 3H-benzoimidazol-5-yl,    then R₂ is not 3-aminophenyl; and-   if R₁ is 1H-indazol-6-yl, then R₂ is not 3-carboxyphenyl or    4-carboxyphenyl.

In some embodiments, R₁ is pyridinyl substituted with one or more groupschosen from

hydroxy;

—NR^(b)R^(c) wherein R^(b) is chosen from hydrogen and C₁-C₆ alkyloptionally substituted with one or two groups chosen from hydroxy and—OC₁-C₄ alkyl and R^(c) is independently chosen from hydrogen and C₁-C₄alkyl optionally substituted with one or two groups chosen from hydroxyand —OC₁-C₄ alkyl;

heterocycloalkyl optionally substituted with one or two groups chosenfrom hydroxy, C₃-C₆ cycloalkyl, C₁-C₄ alkyl, —C₁-C₄ alkyl-OH, —C₁-C₄alkyl-O—C₁-C₄ alkyl, —C₁-C₄ alkyl-NH₂, —N(C₁-C₄ alkyl)(C₁-C₄ alkyl),—NH(C₁-C₄ alkyl), and —OC₁-C₄ alkyl;

—OC₁-C₆ alkyl optionally substituted with one or two groups chosen fromhydroxy, C₃-C₆ cycloalkyl, C₁-C₄ alkyl, —C₁-C₄ alkyl-OH, —C₁-C₄alkyl-O—C₁-C₄ alkyl, —C₁-C₄ alkyl-NH₂, —N(C₁-C₄ alkyl)(C₁-C₄ alkyl),—NH(C₁-C₄ alkyl), and —OC₁-C₄ alkyl;

C₁-C₆ alkyl optionally substituted with one or two groups chosen fromhydroxy, C₃-C₆ cycloalkyl, C₁-C₄ alkyl, —C₁-C₄ alkyl-OH, —C₁-C₄alkyl-O—C₁-C₄ alkyl, —C₁-C₄ alkyl-NH₂, —N(C₁-C₄ alkyl)(C₁-C₄ alkyl),—NH(C₁-C₄ alkyl), and —OC₁-C₄ alkyl; and

pyrazolyl optionally substituted with one or two groups chosen fromhydroxy, C₃-C₆ cycloalkyl, C₁-C₄ alkyl, —C₁-C₄ alkyl-OH, —C₁-C₄alkyl-O—C₁-C₄ alkyl, —C₁-C₄ alkyl-NH₂, —N(C₁-C₄ alkyl)(C₁-C₄ alkyl),—NH(C₁-C₄ alkyl), and —OC₁-C₄ alkyl.

In some embodiments, R₁ is pyridinyl substituted with one or more groupschosen from:

hydroxy;

—NR^(b)R^(c) wherein R^(b) is chosen from hydrogen and C₁-C₆ alkyloptionally substituted with one or two groups chosen from hydroxy and—OC₁-C₄ alkyl and R^(c) is independently chosen from hydrogen and C₁-C₄alkyl optionally substituted with one or two groups chosen from hydroxyand —OC₁-C₄ alkyl;

heterocycloalkyl optionally substituted with one or two groups chosenfrom hydroxy, —OC₁-C₄ alkyl, and C₁-C₄ alkyl;

—OC₁-C₆ alkyl optionally substituted with one or two groups chosen fromhydroxy, —OC₁-C₄ alkyl, —NH₂, —N(C₁-C₄ alkyl)H, and —N(C₁-C₄alkyl)(C₁-C₄ alkyl); and

C₁-C₆ alkyl optionally substituted with hydroxy.

In some embodiments, R₁ is chosen from(2-methyl-2-hydroxypropoxy)pyridin-6-yl, (2-methoxyethoxy)pyridinyl,2-(dimethylamino)ethoxy-3-pyridinyl, hydroxyethoxy-5-pyridinyl,(3-methyl-3-hydroxyazetidine)pyridin-3-yl,(3-methyl-3-hydroxyazetidine)pyridin-2-yl,(3-hydroxyazetidine)pyridin-2-yl, (hydroxy(dimethylethyl))-5-pyridinyl,(4-methyl-4-hydroxypiperidine)pyridin-2-yl,(3-methyl-3-hydroxypiperidine)pyridin-2-yl, 5-morpholinopyridin-2-yl,6-morpholinopyridin-3-yl, ((2-methoxyethyl)(methyl)amino)pyridin-5-yl,((2-hydroxyethyl)(methyl)amino)pyridin-5-yl, 2-methoxy-4-pyridinyl, and2-hydroxy-5-pyridinyl.

In some embodiments, R₁ is pyrazolyl substituted with one or two groupschosen from cycloalkyl, C₁-C₆ alkyl, and C₁-C₆ alkyl substituted withone or more groups chosen from hydroxy and —OC₁-C₄ alkyl.

In some embodiments, R₁ is chosen from (2-hydroxyethyl)-1H-pyrazol-4-yl,(2-hydroxypropyl)-1H-pyrazol-4-yl, (2-methoxyethyl)-1H-pyrazol-4-yl,1-ethyl-1H-pyrazol-4-yl, 1-isopropyl-1H-pyrazol-4-yl,3-cyclopropyl-1H-pyrazol-5-yl, and 1-ethyl-5-methyl-1H-pyrazol-3-yl.

In some embodiments, R₁ is

In some embodiments, A is an optionally substituted pyrazolyl, oxazolyl,pyrrolyl, thiazolyl, or imidazolyl group. In some embodiments, theimidazolyl group is substituted with C₁-C₆ alkyl.

In some embodiments, R₁ is chosen from 1H-benzo[d]imidazol-6-yl,1H-benzo[d]imidazol-5-yl, 1H-indazol-6-yl, 1H-indazol-5-yl,1-methyl-1H-benzo[d]imidazol-6-yl, benzoxazol-6-yl, benzoxazol-5-yl,imidazo[1,2-a]pyridine-6-yl, 1H-indole-6-yl, 1H-indole-5-yl,benzothiazol-6-yl, and benzothiazol-5-yl.

In some embodiments, R₂ is chosen from optionally substitutedheteroaryl, dihydroindolyl optionally substituted with oxo and C₁-C₆alkyl, and dihydrobenzoxazinyl optionally substituted with oxo.

In some embodiments, R₂ is chosen from 2,3-dimethyl-2H-indazol-6-yl,1H-indazolyl-6-yl, 1-methyl-1H-indazol-5-yl, 1-methyl-1H-indazol-6-yl,3,4-dihydro-2H-1,4-benzoxazin-3-one-6-yl, 1,3-benzoxazol-6-yl,3-aminoquinolin-6-yl, 2,3-dihydro-1H-indol-6-yl,1H,2H,3H-pyrido[2,3-b][1,4]oxazin-2-one, benzothiazolyl,2-aminoquinazolin-6-yl, 3,3-dimethylindolin-2-one,2,3-dihydro-1H-indol-2-one, 4-fluoro-1H-indazol-6-yl,5-fluoro-1H-indazol-6-yl, and 3-amino-1H-indazol-6-yl.

In some embodiments, R₂ is chosen from 1H-indazolyl-6-yl,1-methyl-1H-indazol-5-yl, 1-methyl-1H-indazol-6-yl,3,4-dihydro-2H-1,4-benzoxazin-3-one-6-yl, 1,3-benzoxazol-6-yl,3-aminoquinolin-6-yl, and 2,3-dihydro-1H-indol-2-one-6-yl.

Also provided is at least one chemical entity chosen from:

-   N-[6-(1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]-1H-1,3-benzodiazol-6-amine;-   N-[6-(1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]-1H-indazol-6-amine;-   N-[6-(1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]-1-methyl-1H-1,3-benzodiazol-6-amine;-   N-[6-(1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]-1,3-benzoxazol-6-amine;-   N-[6-(1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]-1,3-benzoxazol-5-amine;-   5-{[6-(1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]amino}pyridin-2-ol;-   N-{imidazo[1,2-a]pyridin-6-yl}-6-(1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-amine;-   N-[6-(1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]-1H-indazol-5-amine;-   N-[6-(1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]-1H-indol-6-amine;-   N-[6-(1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]-1H-indol-5-amine;-   N-[6-(1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]-1,3-benzothiazol-6-amine;-   N-[6-(1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]-1,3-benzothiazol-5-amine;-   N-[6-(1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]-2-methoxypyridin-4-amine;-   6-[8-(1H-1,3-benzodiazol-5-ylamino)imidazo[1,2-a]pyrazin-6-yl]-3,4-dihydro-2H-1,4-benzoxazin-3-one;-   2-(4-{[6-(1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]amino}-1H-pyrazol-1-yl)ethan-1-ol;-   3-(4-{[6-(1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]amino}-1H-pyrazol-1-yl)propan-1-ol;-   N-[6-(1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]-1-(2-methoxyethyl)-1H-pyrazol-4-amine;-   1-ethyl-N-[6-(1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]-1H-pyrazol-4-amine;-   N-[6-(1,3-benzoxazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]-1H-1,3-benzodiazol-6-amine;-   N-[6-(1H-1,3-benzodiazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]-1H-indazol-6-amine;-   N-[6-(1-methyl-1H-indazol-5-yl)imidazo[1,2-a]pyrazin-8-yl]-1H-indazol-5-amine;-   N-[6-(3,4-dihydro-2H-1,4-benzoxazin-6-yl)imidazo[1,2-a]pyrazin-8-yl]-1H-indazol-6-amine;-   N-[6-(3-aminoquinolin-6-yl)imidazo[1,2-a]pyrazin-8-yl]-1,3-benzothiazol-5-amine;-   6-{8-[(2-methoxypyridin-4-yl)amino]imidazo[1,2-a]pyrazin-6-yl}-3,4-dihydro-2H-1,4-benzoxazin-3-one;-   N-[6-(2,3-dihydro-1H-indol-6-yl)imidazo[1,2-a]pyrazin-8-yl]-2-methoxypyridin-4-amine;-   N-[6-(1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]-1-(propan-2-yl)-1H-pyrazol-4-amine;-   1-methyl-N-[6-(1-methyl-1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]-1H-1,3-benzodiazol-6-amine;-   3-cyclopropyl-N-[6-(1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]-1H-pyrazol-5-amine;-   N-[6-(1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]-6-(morpholin-4-yl)pyridin-3-amine;-   N-[6-(2,3-dimethyl-2H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]-6-(morpholin-4-yl)pyridin-3-amine;-   5-N-[6-(1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]-2-N-(2-methoxyethyl)-2-N-methylpyridine-2,5-diamine;-   2-[(5-{[6-(1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]amino}pyridin-2-yl)(methyl)amino]ethan-1-ol;

1-[(6-{[6-(1H-indazol-6-yl)imidazo[1,2-a]pyridin-8-yl]amino}pyridin-3-yl)oxy]-2-methylpropan-2-ol;

-   7-(8-{[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]amino}imidazo[1,2-a]pyrazin-6-yl)-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-2-one;-   2-(4-{[6-(3,4-dihydro-2H-1,4-benzoxazin-7-yl)imidazo[1,2-a]pyrazin-8-yl]amino}-1H-pyrazol-1-yl)ethan-1-ol;-   6-(8-{[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]amino}imidazo[1,2-a]pyrazin-6-yl)-3,4-dihydro-2H-1,4-benzoxazin-3-one;-   2-(4-{[6-(1,3-benzothiazol-5-yl)imidazo[1,2-a]pyrazin-8-yl]amino}-1H-pyrazol-1-yl)ethan-1-ol;-   N-[6-(1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]-6-(2-methoxyethoxy)pyridin-3-amine;-   6-(8-{[6-(morpholin-4-yl)pyridin-3-yl]amino}imidazo[1,2-a]pyrazin-6-yl)quinazolin-2-amine;-   2-(4-{[6-(3,4-dihydro-2H-1,4-benzoxazin-6-yl)imidazo[1,2-a]pyrazin-8-yl]amino}-1H-pyrazol-1-yl)ethan-1-ol;

6-[2-(dimethylamino)ethoxy]-N-[6-(1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]pyridin-3-amine;

-   1-(6-{[6-(1H-indazol-6-yl)imidazo[1,2-a]pyridin-8-yl]amino}pyridin-3-yl)-3-methylazetidin-3-ol;-   2-[(5-{[6-(1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]amino}pyridin-2-yl)oxy]ethan-1-ol;-   3,3-dimethyl-6-(8-{[6-(morpholin-4-yl)pyridin-3-yl]amino}imidazo[1,2-a]pyrazin-6-yl)-2,3-dihydro-1H-indol-2-one;-   1-(5-{[6-(1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]amino}pyridin-2-yl)-3-methylazetidin-3-ol;-   1-(6-{[6-(1H-indazol-6-yl)imidazo[1,2-a]pyridin-8-yl]amino}pyridin-3-yl)azetidin-3-ol;-   2-(5-{[6-(1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]amino}pyridin-2-yl)-2-methylpropan-1-ol;-   1-[(5-{[6-(1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]amino}pyridin-2-yl)oxy]-2-methylpropan-2-ol;-   N-[5-(3,4-dihydro-2H-1,4-benzoxazin-6-yl)pyrazolo[1,5-a]pyrimidin-7-yl]-5-(morpholin-4-yl)pyridin-2-amine;-   N-[5-(1-methyl-1H-1,3-benzodiazol-6-yl)pyrazolo[1,5-a]pyrimidin-7-yl]-5-(morpholin-4-yl)pyridin-2-amine;-   6-(7-{[5-(morpholin-4-yl)pyridin-2-yl]amino}pyrazolo[1,5-a]pyrimidin-5-yl)-2,3-dihydro-1H-indol-2-one;-   N-[6-(3,4-dihydro-2H-1,4-benzoxazin-6-yl)imidazo[1,2-a]pyrazin-8-yl]-6-(morpholin-4-yl)pyridin-3-amine;-   N-[6-(3,4-dihydro-2H-1,4-benzoxazin-7-yl)imidazo[1,2-a]pyrazin-8-yl]-6-(morpholin-4-yl)pyridin-3-amine;-   2-[(6-{[5-(1H-indazol-6-yl)pyrazolo[1,5-a]pyrimidin-7-yl]amino}pyridin-3-yl)(methyl)amino]ethan-1-ol;-   6-(7-{[5-(morpholin-4-yl)pyridin-2-yl]amino}pyrazolo[1,5-a]pyrimidin-5-yl)-3,4-dihydro-2H-1,4-benzoxazin-3-one;-   N-[5-(1H-indol-6-yl)pyrazolo[1,5-a]pyrimidin-7-yl]-5-(morpholin-4-yl)pyridin-2-amine;-   6-(8-{[6-(morpholin-4-yl)pyridin-3-yl]amino}imidazo[1,2-a]pyrazin-6-yl)-2,3-dihydro-1H-indol-2-one;-   N-[6-(1-methyl-1H-1,3-benzodiazol-5-yl)imidazo[1,2-a]pyrazin-8-yl]-6-(morpholin-4-yl)pyridin-3-amine;-   2-[(5-{[6-(3,4-dihydro-2H-1,4-benzoxazin-7-yl)imidazo[1,2-a]pyrazin-8-yl]amino}pyridin-2-yl)(methyl)amino]ethan-1-ol;-   N-[6-(1-methyl-1H-1,3-benzodiazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]-6-(morpholin-4-yl)pyridin-3-amine;

1-(5-{[6-(3,4-dihydro-2H-1,4-benzoxazin-6-yl)imidazo[1,2-a]pyrazin-8-yl]amino}pyridin-2-yl)-4-methylpiperidin-4-ol;

-   N-[6-(1H-1,3-benzodiazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]-6-(morpholin-4-yl)pyridin-3-amine;

1-(5-{[6-(3,4-dihydro-2H-1,4-benzoxazin-6-yl)imidazo[1,2-a]pyrazin-8-yl]amino}pyridin-2-yl)azetidin-3-ol;

-   N-[5-(1H-1,3-benzodiazol-6-yl)pyrazolo[1,5-a]pyrimidin-7-yl]-5-(morpholin-4-yl)pyridin-2-amine;-   1-(5-{[6-(1H-indol-6-yl)imidazo[1,2-a]pyrazin-8-yl]amino}pyridin-2-yl)-4-methylpiperidin-4-ol;-   N-[6-(1H-indol-6-yl)imidazo[1,2-a]pyrazin-8-yl]-6-(morpholin-4-yl)pyridin-3-amine;-   6-(8-{[6-(morpholin-4-yl)pyridin-3-yl]amino}imidazo[1,2-a]pyrazin-6-yl)-3,4-dihydro-2H-1,4-benzoxazin-3-one;-   1-ethyl-N-[6-(1H-indazol-6-yl)imidazo[1,2-a]pyridin-8-yl]-5-methyl-1H-pyrazol-3-amine;-   6-[8-({6-[(2-hydroxyethyl)(methyl)amino]pyridin-3-yl}amino)imidazo[1,2-a]pyrazin-6-yl]-3,4-dihydro-2H-1,4-benzoxazin-3-one;-   1-(5-{[6-(1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]amino}pyridin-2-yl)-3-methylpiperidin-3-ol;-   N-[6-(1H-indazol-6-yl)imidazo[1,2-a]pyridin-8-yl]-6-(morpholin-4-yl)pyridazin-3-amine;-   7-(8-{[6-(morpholin-4-yl)pyridin-3-yl]amino}imidazo[1,2-a]pyrazin-6-yl)-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-2-one;-   N-[6-(1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]-6-[4-(propan-2-yl)piperazin-1-yl]pyridin-3-amine;-   N-[6-(4-fluoro-1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]-6-(morpholin-4-yl)pyridin-3-amine;-   2-N-[6-(1H-indazol-6-yl)imidazo[1,2-a]pyridin-8-yl]-5-N-(2-methoxyethyl)-5-N-methylpyridine-2,5-diamine;-   6-(1H-benzo[d]imidazol-6-yl)-N-(5-morpholinopyridin-2-yl)imidazo[1,2-b]pyridazin-8-amine;-   6-(3-amino-1H-indazol-6-yl)-N-(5-morpholinopyridin-2-yl)imidazo[1,2-b]pyridazin-8-amine;-   2-[(6-{[6-(1H-indazol-6-yl)imidazo[1,2-a]pyridin-8-yl]amino}pyridin-3-yl)(methyl)amino]ethan-1-ol;-   1-(5-{[6-(1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]amino}pyridin-2-yl)-4-methylpiperidin-4-ol;-   1-(5-{[6-(1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]amino}pyridin-2-yl)azetidin-3-ol;-   6-(1H-indol-6-yl)-N-(5-morpholinopyridin-2-yl)imidazo[1,2-b]pyridazin-8-amine;    and-   N-[6-(5-fluoro-1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]-6-(morpholin-4-yl)pyridin-3-amine,    and pharmaceutically acceptable salts thereof.

Also provided is at least one chemical entity chosen from:

-   N-[6-(1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]-6-(morpholin-4-yl)pyridin-3-amine;-   N-[6-(2,3-dimethyl-2H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]-6-(morpholin-4-yl)pyridin-3-amine;-   5-N-[6-(1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]-2-N-(2-methoxyethyl)-2-N-methylpyridine-2,5-diamine;    and-   2-[(5-{[6-(1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]amino}pyridin-2-yl)(methyl)amino]ethan-1-ol,    and pharmaceutically acceptable salts thereof.

Also provided is at least one chemical entity chosen from:

-   (3S)-1-(5-{[6-(1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]amino}pyridin-2-yl)-3-methylpiperidin-3-ol,-   (3R)-1-(5-{[6-(1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]amino}pyridin-2-yl)-3-methylpiperidin-3-ol,-   1-(5-{[6-(1H-indol-6-yl)imidazo[1,2-a]pyrazin-8-yl]amino}pyridin-2-yl)-3-methylazetidin-3-ol,-   [(2R)-4-(5-{[6-(1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]amino}pyridin-2-yl)morpholin-2-yl]methanol,-   [(2S)-4-(5-{[6-(1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]amino}pyridin-2-yl)morpholin-2-yl]methanol,-   N-[6-(1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]-2-(morpholin-4-yl)pyrimidin-5-amine,-   1-ethyl-N-(6-{1H-pyrrolo[3,2-b]pyridin-6-yl}imidazo[1,2-a]pyrazin-8-yl)-1H-pyrazol-4-amine,    and-   2-{4-[(6-{1H-pyrrolo[3,2-b]pyridin-6-yl}imidazo[1,2-a]pyrazin-8-yl)amino]-1H-pyrazol-1-yl}ethan-1-ol,    and pharmaceutically acceptable salts thereof.

In all of the foregoing examples, the chemical entities can beadministered alone, as mixtures, or in combination with other activeagents.

Methods for obtaining the novel compounds described herein will beapparent to those of ordinary skill in the art, suitable proceduresbeing described, for example, in the reaction schemes and examplesbelow, and in the references cited herein.

Referring to Reaction Scheme 1, Step 1, an excess (such as about 3.5equivalents) of a compound of Formula 100, where L is a leaving groupsuch as bromide is combined with an aqueous solution of acid (such as48% aqueous hydrogen bromide), and the mixture is stirred at reflux forabout 2 h. The mixture is cooled to about 40° C. and base (such as solidsodium bicarbonate) is added. The reaction mixture is filtered and acompound of Formula 101, where L is a leaving group such as bromide isadded, and the reaction mixture is stirred at reflux for about 16 h. Theproduct, a compound of Formula 102, is isolated and optionally purified.

Referring to Reaction Scheme 1, Step 2, a mixture of a compound ofFormula 102, where L is a leaving group such as bromide is combined withan excess of a compound of Formula 103 (such as about 3 equivalents) andan excess of an organic base (such as about 1.7 equivalents), such asN,N-diisopropylethylamine in a polar solvent such asN,N-dimethylformamide. The reaction mixture is stirred at about 100° C.for about 3 h. The product, a compound of Formula 104, is isolated andoptionally purified.

Referring to Reaction Scheme 1, Step 3, a mixture of a compound ofFormula 104, where L is a leaving group such as bromide is combined withan excess of a compound of Formula 105 (such as 1.1 equivalents) and anaqueous solution of base (such as 1 M aqueous sodium carbonate) in aninert solvent, such as 1,4 dioxane. The reaction mixture is sparged withnitrogen and stirred for about 5 min. The resulting mixture is treatedwith about 0.1 equivalent of tetrakis(triphenylphosphine)palladium(0)and reacted under microwave irradiation at about 135° C. for about 30min. The resulting product, a compound of Formula 106, is isolated andoptionally purified.

Accordingly, provided is a method of treating a patient, for example, amammal, such as a human, having a disease responsive to inhibition ofSyk activity, comprising administrating to the patient having such adisease, an effective amount of at least one chemical entity describedherein.

In some embodiments, the chemical entities described herein may alsoinhibit other kinases, such that disease, disease symptoms, andconditions associated with these kinases is also treated.

Methods of treatment also include inhibiting Syk activity and/orinhibiting B-cell activity, by inhibiting ATP binding or hydrolysis bySyk or by some other mechanism, in vivo, in a patient suffering from adisease responsive to inhibition of Syk activity, by administering aneffective concentration of at least one chemical entity chosen describedherein. An example of an effective concentration would be thatconcentration sufficient to inhibit Syk activity in vitro. An effectiveconcentration may be ascertained experimentally, for example by assayingblood concentration of the chemical entity, or theoretically, bycalculating bioavailability.

In some embodiments, the condition responsive to inhibition of Sykactivity and/or B-cell activity is cancer, an allergic disorder and/oran autoimmune and/or inflammatory disease, and/or an acute inflammatoryreaction.

Also provided is a method of treating a patient having cancer, anallergic disorder and/or an autoimmune and/or inflammatory disease,and/or an acute inflammatory reaction, by administering an effectiveamount of at least one chemical entity described herein.

In some embodiments, the conditions and diseases that can be affectedusing chemical entities described herein, include, but are not limitedto: allergic disorders, including but not limited to eczema, allergicrhinitis or coryza, hay fever, bronchial asthma, urticaria (hives) andfood allergies, and other atopic conditions; autoimmune and/orinflammatory diseases, including but not limited to psoriasis, Crohn'sdisease, irritable bowel syndrome, Sjogren's disease, tissue graftrejection, and hyperacute rejection of transplanted organs, asthma,systemic lupus erythematosus (and associated glomerulonephritis),dermatomyositis, multiple sclerosis, scleroderma, vasculitis(ANCA-associated and other vasculitides), autoimmune hemolytic andthrombocytopenic states, Goodpasture's syndrome (and associatedglomerulonephritis and pulmonary hemorrhage), atherosclerosis,rheumatoid arthritis, chronic Idiopathic thrombocytopenic purpura (ITP),Addison's disease, Parkinson's disease, Alzheimer's disease, diabetes,septic shock, myasthenia gravis, and the like; acute inflammatoryreactions, including but not limited to skin sunburn, inflammatorypelvic disease, inflammatory bowel disease, urethritis, uvitis,sinusitis, pneumonitis, encephalitis, meningitis, myocarditis,nephritis, osteomyelitis, myositis, hepatitis, gastritis, enteritis,dermatitis, gingivitis, appendicitis, pancreatitis, and cholocystitis;polycystic kidney disease, and cancer, including but not limited to,B-cell lymphoma, lymphoma (including Hodgkin's and non-Hodgkinslymphoma), hairy cell leukemia, multiple myeloma, chronic and acutemyelogenous leukemia, and chronic and acute lymphocytic leukemia.

Syk is a known inhibitor of apoptosis in lymphoma B-cells. Defectiveapoptosis contributes to the pathogenesis and drug resistance of humanleukemias and lymphomas. Thus, further provided is a method of promotingor inducing apoptosis in cells expressing Syk comprising contacting thecell with at least one chemical entity described herein.

Also provided are methods of treatment in which at least one chemicalentity described herein is the only active agent given to a patient andalso includes methods of treatment in which at least one chemical entitydescribed herein is given to a patient in combination with one or moreadditional active agents.

Thus in some embodiments, a method of treating cancer, an allergicdisorder and/or an autoimmune and/or inflammatory disease, and/or anacute inflammatory reaction comprises administering to a patient in needthereof an effective amount of at least one chemical entity describedherein, together with a second active agent, which can be useful fortreating a cancer, an allergic disorder and/or an autoimmune and/orinflammatory disease, and/or an acute inflammatory reaction. For examplethe second agent may be an anti-inflammatory agent. Treatment with thesecond active agent may be prior to, concomitant with, or followingtreatment with at least one chemical entity described herein. In someembodiments, at least one chemical entity described herein is combinedwith another active agent in a single dosage form. Suitable antitumortherapeutics that may be used in combination with at least one chemicalentity described herein include, but are not limited to,chemotherapeutic agents, for example mitomycin C, carboplatin, taxol,cisplatin, paclitaxel, etoposide, doxorubicin, or a combinationcomprising at least one of the foregoing chemotherapeutic agents.Radiotherapeutic antitumor agents may also be used, alone or incombination with chemotherapeutic agents.

Chemical entities described herein can be useful as chemosensitizingagents, and, thus, can be useful in combination with otherchemotherapeutic drugs, in particular, drugs that induce apoptosis.

A method for increasing sensitivity of cancer cells to chemotherapy,comprising administering to a patient undergoing chemotherapy achemotherapeutic agent together with at least one chemical entitydescribed herein in an amount sufficient to increase the sensitivity ofcancer cells to the chemotherapeutic agent is also provided herein.

Examples of other chemotherapeutic drugs that can be used in combinationwith chemical entities described herein include topoisomerase Iinhibitors (camptothesin or topotecan), topoisomerase II inhibitors(e.g. daunomycin and etoposide), alkylating agents (e.g.cyclophosphamide, melphalan and BCNU), tubulin directed agents (e.g.taxol and vinblastine), and biological agents (e.g. antibodies such asanti CD20 antibody, IDEC 8, immunotoxins, and cytokines).

In some embodiments, the chemical entities described herein are used incombination with Rituxan® (Rituximab) or other agents that work byselectively depleting CD20+ B-cells.

Included herein are methods of treatment in which at least one chemicalentity described herein is administered in combination with ananti-inflammatory agent. Anti-inflammatory agents include but are notlimited to NSAIDs, non-specific and COX-2 specific cyclooxygenase enzymeinhibitors, gold compounds, corticosteroids, methotrexate, tumornecrosis factor receptor (TNF) receptors antagonists, immunosuppressantsand methotrexate.

Examples of NSAIDs include, but are not limited to ibuprofen,flurbiprofen, naproxen and naproxen sodium, diclofenac, combinations ofdiclofenac sodium and misoprostol, sulindac, oxaprozin, diflunisal,piroxicam, indomethacin, etodolac, fenoprofen calcium, ketoprofen,sodium nabumetone, sulfasalazine, tolmetin sodium, andhydroxychloroquine. Examples of NSAIDs also include COX-2 specificinhibitors (i.e., a compound that inhibits COX-2 with an IC₅₀ that is atleast 50-fold lower than the IC₅₀ for COX-1) such as celecoxib,valdecoxib, lumiracoxib, etoricoxib and/or rofecoxib.

In some embodiments, the anti-inflammatory agent is a salicylate.Salicylates include but are not limited to acetylsalicylic acid oraspirin, sodium salicylate, and choline and magnesium salicylates.

The anti-inflammatory agent may also be a corticosteroid. For example,the corticosteroid may be chosen from cortisone, dexamethasone,methylprednisolone, prednisolone, prednisolone sodium phosphate, andprednisone.

In some embodiments, the anti-inflammatory therapeutic agent is a goldcompound such as gold sodium thiomalate or auranofin.

In some embodiments, the anti-inflammatory agent is a metabolicinhibitor such as a dihydrofolate reductase inhibitor, such asmethotrexate or a dihydroorotate dehydrogenase inhibitor, such asleflunomide.

In some embodiments, combinations in which at least oneanti-inflammatory compound is an anti-C5 monoclonal antibody (such aseculizumab or pexelizumab), a TNF antagonist, such as entanercept, orinfliximab, which is an anti-TNF alpha monoclonal antibody are used.

In some embodiments, combinations in which at least one active agent isan immunosuppressant compound such as methotrexate, leflunomide,cyclosporine, tacrolimus, azathioprine, or mycophenolate mofetil areused.

Dosage levels of the order, for example, of from 0.1 mg to 140 mg perkilogram of body weight per day can be useful in the treatment of theabove-indicated conditions (0.5 mg to 7 g per patient per day). Theamount of active ingredient that may be combined with the vehicle toproduce a single dosage form will vary depending upon the host treatedand the particular mode of administration. Dosage unit forms willgenerally contain from 1 mg to 500 mg of an active ingredient.

Frequency of dosage may also vary depending on the compound used and theparticular disease treated. In some embodiments, for example, for thetreatment of an allergic disorder and/or autoimmune and/or inflammatorydisease, a dosage regimen of 4 times daily or less is used. In someembodiments, a dosage regimen of 1 or 2 times daily is used. It will beunderstood, however, that the specific dose level for any particularpatient will depend upon a variety of factors including the activity ofthe specific compound employed, the age, body weight, general health,sex, diet, time of administration, route of administration, and rate ofexcretion, drug combination and the severity of the particular diseasein the patient undergoing therapy.

A labeled form of a chemical entity described herein can be used as adiagnostic for identifying and/or obtaining compounds that have thefunction of modulating an activity of a kinase as described herein. Thechemical entities described herein may additionally be used forvalidating, optimizing, and standardizing bioassays.

By “labeled” herein is meant that the compound is either directly orindirectly labeled with a label which provides a detectable signal,e.g., radioisotope, fluorescent tag, enzyme, antibodies, particles suchas magnetic particles, chemiluminescent tag, or specific bindingmolecules, etc. Specific binding molecules include pairs, such as biotinand streptavidin, digoxin and antidigoxin etc. For the specific bindingmembers, the complementary member would normally be labeled with amolecule which provides for detection, in accordance with knownprocedures, as outlined above. The label can directly or indirectlyprovide a detectable signal.

EXAMPLES

The invention is further illustrated by the following non-limitingexamples.

In the examples below, the following abbreviations have the followingmeanings. If an abbreviation is not defined, it has its generallyaccepted meaning.

DME=dimethyl ether

DMEM=Dulbecco's modified Eagle's medium

DMF=N,N-dimethylformamide

DMSO=dimethylsulfoxide

Et₂O=diethylether

g=gram

h=hour

mg=milligram

min=minutes

mL=milliliter

mmol=millimoles

mM=millimolar

ng=nanogram

nm=nanometer

nM=nanomolar

PBS=phosphate buffered saline

μL=microliter

μM=micromolar

Example I Preparation of6-(1H-indazol-6-yl)-N-(1-isopropyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-amine(5)

Preparation of 1-isopropyl-4-nitro-1H-pyrazole (1)

Di-tert-butyl azodicarboxylate (1.59 g, 6.91 mmol) was added to asolution of 4-nitro-1H-pyrazole (601 mg, 5.32 mmol), 2-propanol (319 mg,5.32 mmol) and triphenylphosphine (1.67 g, 6.36 mmol) in tetrahydrofuran(25 mL) over 3 minutes and the mixture was stirred at room temperaturefor 16 h. After this time, the reaction was concentrated under reducedpressure and the resulting residue purified by chromatography (silica,gradient, 1:4 ethyl acetate/heptane to 7:3 ethyl acetate/heptane) toafford 1-isopropyl-4-nitro-1H-pyrazole (1) (1.23 g, >100%) as an impureoff-white solid, which was used without further purification: ¹H NMR(300 MHz, DMSO-d₆) δ 8.91 (s, 1H), 8.24 (s, 1H), 4.58 (m, 1H), 1.42 (d,J=6.6 Hz, 6H).

Preparation of 1-isopropyl-1H-pyrazole-4-amine (2)

A suspension of impure 1-isopropyl-4-nitro-1H-pyrazole (1) (1.23 g),from above, in ethanol (50 mL) was treated with 10% palladium on carbon(400 mg, 50% water by weight) and shaken under a hydrogen atmosphere (35psi) at room temperature for 1 h. After this time, the reaction wasfiltered through diatomaceous earth and the filtrate concentrated underreduced pressure to afford 1-isopropyl-1H-pyrazole-4-amine (2) (1.15 g)as an impure off-white solid, which was used without furtherpurification: ¹H NMR (300 MHz, DMSO-d₆) δ 7.02 (s, 1H), 6.87 (s, 1H),4.26 (m, 1H), 3.72 (bs, 2H), 1.42 (d, J=6.6 Hz, 6H).

Preparation of 6,8-dibromoimidazo[1,2-a]pyrazine (3)

A 1-L four-neck round bottom flask equipped with a temperature probe,mechanical stirrer and reflux condenser was charged with2-bromo-1,1-diethoxyethane (68.1 g, 346 mmol) and 48% aqueous hydrogenbromide (11.3 mL, 99.2 mmol), and the reaction mixture was stirred atreflux for 2 h. The resulting mixture was allowed to cool to 40° C. andsolid sodium bicarbonate (8.50 g, 101 mmol) was added in small portionsuntil gas evolution was observed to cease. Caution: initial addition ofsodium bicarbonate to the warm solution resulted in vigorous gasevolution (foaming). The resulting suspension was filtered into a 1-Lfour-neck round bottomed flask and the filter cake was washed withethanol (200 mL). The flask was equipped with a temperature probe,mechanical stirrer and reflux condenser. 3,5-Dibromopyrazin-2-amine(50.0 g, 198 mmol) was added and the reaction mixture was heated atreflux, with vigorous stirring, for 16 h. After this time, thesuspension was cooled to 0° C. and filtered. The filter cake was washedwith cold ethanol (50 mL), dried under vacuum and added to a 1-Lthree-neck round bottomed flask equipped with a mechanical stirrer.Water (200 mL) was added and the vigorously stirred suspension wastreated portion-wise with solid potassium carbonate (27.4 g, 198 mmol).Caution: gas evolution upon the addition of potassium carbonateobserved. After stirring for 30 min, the resulting precipitate wasisolated by filtration and the filter cake washed with water (100 mL)followed by ethanol (50 mL). The filter cake was dried at 50° C. to aconstant weight, under vacuum to provide6,8-dibromoimidazo[1,2-a]pyrazine (3) (52.0 g, 94%) as a light yellowsolid: ¹H NMR (300 MHz, DMSO-d₆) δ 9.02 (s, 1H), 8.23 (s, 1H), 7.90 (s,1H).

Preparation of6-bromo-N-(1-isopropyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-amine (4)

A mixture of impure 1-isopropyl-1H-pyrazole-4-amine (2) (1.00 g), fromabove, 6,8-dibromoimidazo[1,2-a]pyrazine (3) (750 mg, 2.71 mmol), andN,N-diisopropylethylamine (526 mg, 4.16 mmol) in DMF (20 mL) was stirredat 100° C. for 3 h. After this time, the reaction was cooled to roomtemperature and poured into ice water (200 mL). The resulting suspensionwas filtered and the filter cake dried to a constant weight under vacuumto afford impure6-bromo-N-(1-isopropyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-amine (4)(1.26 g) as an off-white solid, which was used

without further purification: ¹H NMR (300 MHz, DMSO-d₆) δ 10.26 (s, 1H),8.14 (s, 1H), 8.08 (s, 1H), 7.90 (s, 1H), 7.77 (s, 1H), 7.59 (s, 1H),4.49 (m, 1H), 1.40 (d, 6H); ESI MS m/z 323.3 [M+H]⁺.

Preparation of6-(1H-indazol-6-yl)-N-(1-isopropyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-amine(5)

A mixture of impure6-bromo-N-(1-isopropyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-amine (4)(195 mg), from above, and 1H-indazol-6-ylboronic acid (159 mg, 0.650mmol) in 1 M aqueous sodium carbonate (1.3 mL) and 1,4-dioxane (3.5 mL)was sparged with nitrogen while stirring for 5 min.Tetrakis(triphenylphosphine)palladium(0) (69 mg, 0.060 mmol) was thenadded and the resulting mixture heated under microwave irradiation at135° C. for 30 min. After this time, the reaction was diluted withmethylene chloride (30 mL) and water (20 mL), and filtered throughdiatomaceous earth. The filtrate layers were separated and the aqueousphase was extracted with a mixture of 9:1 methylene chloride/methanol(100 mL). The combined organic layers were concentrated under reducedpressure and the resulting residue was purified by chromatography(silica, gradient, methylene chloride to 8:2 methylenechloride/methanol), then trituration with acetonitrile to afford6-(1H-indazol-6-yl)-N-(1-isopropyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-amine(5) (85 mg, 35%) as a yellow solid: mp>250° C.; ¹H NMR (300 MHz,DMSO-d₆) δ 13.23 (s, 1H), 9.95 (s, 1H), 8.59 (s, 1H), 8.24 (s, 1H), 8.18(s, 1H), 8.10 (s, 1H), 8.00 (s, 1H), 7.97 (d, J=1.2 Hz, 1H), 7.85 (d,J=8.7 Hz, 1H), 7.75 (dd, J=8.7, 1.2 Hz, 1H), 7.62 (s, 1H), 4.52 (m, 1H),1.47 (d, J=6.6 Hz, 6H); ESI MS m/z 359.4 [M+H]⁺; HPLC, 5.37 min, >99%(AUC).

Example 2

The following compounds were prepared using procedures similar to thosedescribed above. Those of ordinary skill in the art of organic synthesiswill recognize when starting materials or reaction conditions should bevaried to obtain the desired compound.

MS data reported in this example was obtained as follows:

MS conditions: Electrospray MS is performed on a MICROMASS LCT equippedwith a LockSpray source for accurate mass measurements. Spectra areacquired in positive ion mode from 100-1000 Da at an acquisition rate of1 spectrum/0.9s with a 0.1s interscan delay. The instrument is tuned fora resolution of 5000 (FWHM). Every 5^(th) scan is taken from thereference position of the Lockspray source. Leucine enkephalin (556.2771[M+H]⁺) is used as the reference, or lock mass.

Structure Name [M + H]⁺

N-[6-(1H-indazol-6-yl)imidazo[1,2- a]pyrazin-8-yl]-1H-1,3-benzodiazol-6-amine 367.3

N-[6-(1H-indazol-6-yl)imidazo[1,2- a]pyrazin-8-yl]-1H-indazol-6-amine367.3

N-[6-(1H-indazol-6-yl)imidazo[1,2- a]pyrazin-8-yl]-1-methyl-1H-1,3-benzodiazol-6-amine 381.3

N-[6-(1H-indazol-6-yl)imidazo[1,2- a]pyrazin-8-yl]-1,3-benzoxazol-6-amine 368.3

N-[6-(1H-indazol-6-yl)imidazo[1,2- a]pyrazin-8-yl]-1H-1,3-benzoxazol-5-amine 368.3

5-{[6-(1H-indazol-6-yl)imidazo[1,2- a]pyrazin-8-yl]amino}pyridin-2-ol344.3

N-{imidazo[1,2-a]pyridin-6-yl}-6- (1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-amine 367.3

N-[6-(1H-indazol-6-yl)imidazo[1,2- a]pyrazin-8-yl]-1H-indazol-5-amine367.3

N-[6-(1H-indazol-6-yl)imidazo[1,2- a]pyrazin-8-yl]-1H-indol-6-amine366.3

N-[6-(1H-indazol-6-yl)imidazo[1,2- a]pyrazin-8-yl]-1H-indol-5-amine366.3

N-[6-(1H-indazol-6-yl)imidazo[1,2- a]pyrazin-8-yl]-1,3-benzothiazol-6-amine 384.3

N-[6-(1H-indazol-6-yl)imidazo[1,2- a]pyrazin-8-yl]-1,3-benzothiazol-5-amine 384.3

N-[6-(1H-indazol-6-yl)imidazo[1,2- a]pyrazin-8-yl]-2-methoxypyridin-4-amine 358.3

6-[8-(1H-1,3-benzodiazol-5- ylamino)imidazo[1,2-a]pyrazin-6-yl]-3,4-dihydro-2H-1,4-benzoxazin- 3-one 398.1

2-(4-{[6-(1H-indazol-6- yl)imidazo[1,2-a]pyrazin-8-yl]amino}-1H-pyrazol-1-yl)ethan-1- ol 361.4

3-(4-{[6-(1H-indazol-6- yl)imidazo[1,2-a]pyrazin-8-yl]amino}-1H-pyrazol-1-yl)propan- 1-ol 375.2

N-[6-(1H-indazol-6-yl)imidazo[1,2- a]pyrazin-8-yl]-1-(2-methoxyethyl)-1H-pyrazol-4-amine 375.4

1-ethyl-N-[6-(1H-indazol-6- yl)imidazo[1,2-a]pyrazin-8-yl]-1H-pyrazol-4-amine 345

N-[6-(1,3-benzoxazol-6- yl)imidazo[1,2-a]pyrazin-8-yl]-1H-1,3-benzodiazol-6-amine 368.2

N-[6-(1H-1,3-benzodiazol-6- yl)imidazo[1,2-a]pyrazin-8-yl]-1H-indazol-6-amine 367.1

N-[6-(1-methyl-1H-indazol-5- yl)imidazo[1,2-a]pyrazin-8-yl]-1H-indazol-5-amine 381.3

N-[6-(3,4-dihydro-2H-1,4- benzoxazin-6-yl)imidazo[1,2-a]pyrazin-8-yl]-1H-indazol-6-amine 384.3

N-[6-(3-aminoquinolin-6- yl)imidazo[1,2-a]pyrazin-8-yl]-1,3-benzothiazol-5-amine 410.3

6-{8-[(2-methoxypyridin-4- yl)amino]imidazo[1,2-a]pyrazin-6-yl}-3,4-dihydro-2H-1,4-benzoxazin- 3-one 389.7

N-[6-(2,3-dihydro-1H-indol-6- yl)imidazo[1,2-a]pyrazin-8-yl]-2-methoxypyridin-4-amine 359.3

N-[6-(1H-indazol-6-yl)imidazo[1,2- a]pyrazin-8-yl]-1-(propan-2-yl)-1H-pyrazol-4-amine 359.4

1-methyl-N-[6-(1-methyl-1H- indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]-1H-1,3-benzodiazol-6-amine 395.1

3-cyclopropyl-N-[6-(1H-indazol-6- yl)imidazo[1,2-a]pyrazin-8-yl]-1H-pyrazol-5-amine 356.4

N-[6-(1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]-6-(morpholin-4-yl)pyridin-3- amine 413.2

N-[6-(2,3-dimethyl-2H-indazol-6- yl)imidazo[1,2-a]pyrazin-8-yl]-6-(morpholin-4-yl)pyridin-3-amine 441.2

5-N-[6-(1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]-2-N-(2-methoxyethyl)-2-N- methylpyridine-2,5-diamine415.6

1-[(6-{[6-(1H-indazol-6-yl)imidazo[1,2-a]pyridin-8-yl]amino}pyridin-3-yl)oxy]-2- methylpropan-2-ol 415.6

7-(8-{[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]amino}imidazo[1,2-a]pyrazin-6-yl)-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-2-one 393.2

2-(4-{[6-(3,4-dihydro-2H-1,4-benzoxazin-7-yl)imidazo[1,2-a]pyrazin-8-yl]amino}-1H- pyrazol-1-yl)ethan-1-ol 378.6

6-(8-{[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]amino}imidazo[1,2-a]pyrazin-6-yl)-3,4-dihydro-2H-1,4-benzoxazin-3-one 392.4

2-(4-{[6-(1,3-benzothiazol-5- yl)imidazo[1,2-a]pyrazin-8-yl]amino}-1H-pyrazol-1-yl)ethan-1-ol 378.5

N-[6-(1H-indazol-6-yl)imidazo[1,2- a]pyrazin-8-yl]-6-(2-methoxyethoxy)pyridin-3-amine 402.4

6-(8-{[6-(morpholin-4-yl)pyridin-3- yl]amino}imidazo[1,2-a]pyrazin-6-yl)quinazolin-2-amine 440.3

2-(4-{[6-(3,4-dihydro-2H-1,4-benzoxazin-6-yl)imidazo[1,2-a]pyrazin-8-yl]amino}-1H- pyrazol-1-yl)ethan-1-ol 378.6

6-[2-(dimethylamino)ethoxy]-N-[6-(1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8- yl]pyridin-3-amine 415.4

1-(6-{[6-(1H-indazol-6-yl)imidazo[1,2-a]pyridin-8-yl]amino}pyridin-3-yl)-3- methylazetidin-3-ol 412.4

2-[(5-{[6-(1H-indazol-6-yl)imidazo[1,2- a]pyrazin-8-yl]amino}pyridin-2-yl)oxy]ethan-1-ol 388.5

3,3-dimethyl-6-(8-{[6-(morpholin-4- yl)pyridin-3-yl]amino}imidazo[1,2-a]pyrazin-6-yl)-2,3-dihydro-1H-indol-2-one 456.4

1-(5-{[6-(1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]amino}pyridin-2-yl)-3- methylazetidin-3-ol 413.4

1-(6-{[6-(1H-indazol-6-yl)imidazo[1,2-a]pyridin-8-yl]amino}pyridin-3-yl)azetidin- 3-ol 398.1

2-(5-{[6-(1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]amino}pyridin-2-yl)-2- methylpropan-1-ol 400.2

1-[(5-{[6-(1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]amino}pyridin-2-yl)oxy]-2- methylpropan-2-ol 416.7

N-[5-(3,4-dihydro-2H-1,4-benzoxazin-6-yl)pyrazolo[1,5-a]pyrimidin-7-yl]-5- (morpholin-4-yl)pyridin-2-amine429.47

N-[5-(1-methyl-1H-1,3-benzodiazol-6-yl)pyrazolo[1,5-a]pyrimidin-7-yl]-5- (morpholin-4-yl)pyridin-2-amine427.1

6-(7-{[5-(morpholin-4-yl)pyridin-2-yl]amino}pyrazolo[1,5-a]pyrimidin-5-yl)- 2,3-dihydro-1H-indol-2-one428.1

N-[6-(3,4-dihydro-2H-1,4-benzoxazin-6- yl)imidazo[1,2-a]pyrazin-8-yl]-6-(morpholin-4-yl)pyridin-3-amine 430.3

N-[6-(3,4-dihydro-2H-1,4-benzoxazin-7- yl)imidazo[1,2-a]pyrazin-8-yl]-6-(morpholin-4-yl)pyridin-3-amine 430.3

2-[(6-{[5-(1H-indazol-6-yl)pyrazolo[1,5-a]pyrimidin-7-yl]amino}pyridin-3- yl)(methyl)amino]ethan-1-ol 401.1

6-(7-{[5-(morpholin-4-yl)pyridin-2-yl]amino}pyrazolo[1,5-a]pyrimidin-5-yl)-3,4-dihydro-2H-1,4-benzoxazin-3-one 444.6

N-[5-(1H-indol-6-yl)pyrazolo[1,5-a]pyrimidin-7-yl]-5-(morpholin-4-yl)pyridin- 2-amine 412.4

6-(8-{[6-(morpholin-4-yl)pyridin-3-yl]amino}imidazo[1,2-a]pyrazin-6-yl)-2,3- dihydro-1H-indol-2-one 428.2

N-[6-(1-methyl-1H-1,3-benzodiazol-5- yl)imidazo[1,2-a]pyrazin-8-yl]-6-(morpholin-4-yl)pyridin-3-amine 427

2-[(5-{[6-(3,4-dihydro-2H-1,4-benzoxazin- 7-yl)imidazo[1,2-a]pyrazin-8-yl]amino}pyridin-2-yl)(methyl)amino]ethan- 1-ol 418.6

N-[6-(1-methyl-1H-1,3-benzodiazol-6- yl)imidazo[1,2-a]pyrazin-8-yl]-6-(morpholin-4-yl)pyridin-3-amine 427

1-(5-{[6-(3,4-dihydro-2H-1,4-benzoxazin- 6-yl)imidazo[1,2-a]pyrazin-8-yl]amino}pyridin-2-yl)-4-methylpiperidin-4- ol 458.2

N-[6-(1H-1,3-benzodiazol-6- yl)imidazo[1,2-a]pyrazin-8-yl]-6-(morpholin-4-yl)pyridin-3-amine 413.3

1-(5-{[6-(3,4-dihydro-2H-1,4-benzoxazin- 6-yl)imidazo[1,2-a]pyrazin-8-yl]amino}pyridin-2-yl)azetidin-3-ol 416.7

N-[5-(1H-1,3-benzodiazol-6- yl)pyrazolo[1,5-a]pyrimidin-7-yl]-5-(morpholin-4-yl)pyridin-2-amine 413.4

1-(5-{[6-(1H-indol-6-yl)imidazo[1,2-a]pyrazin-8-yl]amino}pyridin-2-yl)-4- methylpiperidin-4-ol 440.3

N-[6-(1H-indol-6-yl)imidazo[1,2-a]pyrazin-8-yl]-6-(morpholin-4-yl)pyridin-3-amine 412.2

6-(8-{[6-(morpholin-4-yl)pyridin-3-yl]amino}imidazo[1,2-a]pyrazin-6-yl)-3,4-dihydro-2H-1,4-benzoxazin-3-one 444.8

1-ethyl-N-[6-(1H-indazol-6-yl)imidazo[1,2-a]pyridin-8-yl]-5-methyl-1H-pyrazol-3- amine 358.2

6-[8-({6-[(2- hydroxyethyl)(methyl)amino]pyridin-3-yl}amino)imidazo[1,2-a]pyrazin-6-yl]-3,4-dihydro-2H-1,4-benzoxazin-3-one 432.4

1-(5-{[6-(1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]amino}pyridin-2-yl)-3- methylpiperidin-3-ol 441.2

N-[6-(1H-indazol-6-yl)imidazo[1,2-a]pyridin-8-yl]-6-(morpholin-4-yl)pyridazin- 3-amine 413.4

7-(8-{[6-(morpholin-4-yl)pyridin-3-yl]amino}imidazo[1,2-a]pyrazin-6-yl)-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-2-one 445.5

N-[6-(1H-indazol-6-yl)imidazo[1,2- a]pyrazin-8-yl]-6-[4-(propan-2-yl)piperazin-1-yl]pyridin-3-amine 454.1

N-[6-(4-fluoro-1H-indazol-6- yl)imidazo[1,2-a]pyrazin-8-yl]-6-(morpholin-4-yl)pyridin-3-amine 431.4

2-N-[6-(1H-indazol-6-yl)imidazo[1,2-a]pyridin-8-yl]-5-N-(2-methoxyethyl)-5-N- methylpyridine-2,5-diamine414.2

6-(1H-benzo[d]imidazol-6-yl)-N-(5- morpholinopyridin-2-yl)imidazo[1,2-b]pyridazin-8-amine 413.4

6-(3-amino-1H-indazol-6-yl)-N-(5- morpholinopyridin-2-yl)imidazo[1,2-b]pyridazin-8-amine 428.1

2-[(6-{[6-(1H-indazol-6-yl)imidazo[1,2- a]pyridin-8-yl]amino}pyridin-3-yl)(methyl)amino]ethan-1-ol 400.2

1-(5-{[6-(1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]amino}pyridin-2-yl)-4- methylpiperidin-4-ol 441.2

1-(5-{[6-(1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]amino}pyridin-2-yl)azetidin- 3-ol 399.3

6-(1H-indol-6-yl)-N-(5-morpholinpyridin-2-yl)imidazo[1,2-b]pyridazin-8-amine 412.3

N-[6-(5-fluoro-1H-indazol-6- yl)imidazo[1,2-a]pyrazin-8-yl]-6-(morpholin-4-yl)pyridin-3-amine 431.5

(3S)-1-(5-{[6-(1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]amino}pyridin-2-yl)-3- methylpiperidin-3-ol 441.2

(3R)-1-(5-{[6-(1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]amino}pyridin-2-yl)-3- methylpiperidin-3-ol 441.2

1-(5-{[6-(1H-indol-6-yl)imidazo[1,2-a]pyrazin-8-yl]amino}pyridin-2-yl)-3- methylazetidin-3-ol 412.4

[(2R)-4-(5-{[6-(1H-indazol-6- yl)imidazo[1,2-a]pyrazin-8-yl]amino}pyridin-2-yl)morpholin-2- yl]methanol 443.5

[(2S)-4-(5-{[6-(1H-indazol-6- yl)imidazo[1,2-a]pyrazin-8-yl]amino}pyridin-2-yl)morpholin-2- yl]methanol 443.4

N-[6-(1H-indazol-6-yl)imidazo[1,2- a]pyrazin-8-yl]-2-(morpholin-4-yl)pyrimidin-5-amine 414.5

1-ethyl-N-(6-{1H-pyrrolo[3,2-b]pyridin-6-yl}imidazo[1,2-a]pyrazin-8-yl)-1H-pyrazol- 4-amine 344.9

2-{4-[(6-{1H-pyrrolo[3,2-b]pyridin-6-yl}imidazo[1,2-a]pyrazin-8-yl)amino]-1H- pyrazol-1-yl}ethan-1-ol 361.6

Example 3 Biochemical Syk Assay

A generalized procedure for one standard biochemical Syk Kinase Assaythat can be used to test compounds disclosed in this application is asfollows.

A master mix minus Syk enzyme is prepared containing 1× Cell Signalingkinase buffer (25 mM Tris-HCl, pH 7.5, 5 mM beta-glycerophosphate, 2 mMdithiothreitol, 0.1 mM Na₃VO₄, 10 mM MgCl₂), 0.5 μM Promega PTKBiotinylated peptide substrate 1, 0.01% casein, 0.01% Triton-X100, and0.25% glycerol. A master mix plus Syk enzyme is prepared containing 1×Cell Signaling kinase buffer, 0.5 μM PTK Biotinylated peptide substrate1, 0.01% casein, 0.01% Triton-X100, 0.25% glycerol and 0.4 ng/well Sykenzyme. Syk enzyme is purchased from Cell Signaling Technologies,expressed in baculovirus and is an N-terminally GST-tagged full lengthhuman wildtype Syk (accession number NM-00377). The Syk protein waspurified in one step using glutathione-agarose. The purity of the finalprotein preparation was assessed by SDS-PAGE and Coomassie staining. Asolution of 200 μM ATP is prepared in water and adjusted to pH 7.4 with1N NaOH. A quantity of 1.25 μL of compounds in 5% DMSO is transferred toa 96-well ½ area Costar polystyrene plate Compounds are tested singlyand with an 11-point dose-responsive curve (starting concentration is10-1 μM; 1:2 dilution). A quantity of 18.75 μL of master mix minusenzyme (as a negative control) and master mix plus enzyme is transferredto appropriate wells in 96-well ½ area costar polystyrene plate. 5 μL of200 μM ATP is added to that mixture in the 96-well ½ area Costarpolystyrene plate for final ATP concentration of 40 μM. The reaction isallowed to incubate for 1 hour at room temperature. The reaction isstopped with Perkin Elmer 1× detection buffer containing 30 mM EDTA, 80nM SA-APC, and 4 nM PT66 Ab. The plate is read using time-resolvedfluorescence with a Perkin Elmer Envision using excitation filter 330nm, emission filter 665 nm, and 2^(nd) emission filter 615 nm. IC₅₀values are subsequently calculated using a linear regression algorithm.

Example 4 Ramos Cell pBLNK(Y96) Assay

Another generalized procedure for a standard cellular Syk Kinase Assaythat can be used to test compounds disclosed in this application is asfollows.

Ramos cells are serum starved at 2×10⁶ cells/ml in serum-free RPMI for 1hour in an upright T175 Falcon TC flask. Cells are centrifuged (1100rpm×5 min) and incubated at a density of 0.5×10⁷ cells/ml in thepresence of test compound or DMSO controls for 1 hr at 37° C. Cells arethen stimulated by incubating with 10 μg/ml anti-human IgM F(ab)₂ for 5minutes at 37° C. Cells are pelleted, lysed in 40 ul cell lysis buffer,and mixed with Invitrogen SDS-PAGE loading buffer. 20 ul of cell lysatefor each sample are subject to SDS-PAGE and western blotting withanti-phosphoBLNK(Tyr96) antibody (Cell Signaling Technology #3601) toassess Syk activity and anti-Syk antibody (BD Transduction Labs #611116)to control for total protein load in each lysate. The images aredetected using fluorescent secondary detection systems and the LiCorOdyssey software.

Example 5 B-Cell Proliferation Assay

A generalized procedure for a standard cellular B-cell proliferationassay that can be used to test compounds disclosed in this applicationis as follows.

B-cells are purified from spleens of 8-16 week old Balb/c mice using aB-cell isolation kit (Miltenyi Biotech, Cat # 130-090-862). Testcompounds are diluted in 0.25% DMSO and incubated with 2.5×10⁵ purifiedmouse splenic B-cells for 30 min prior to addition of 10 μg/ml of ananti-mouse IgM antibody (Southern Biotechnology Associates Cat #1022-01)in a final volume of 100 μl. Following 24 hr incubation, 1 μCi³H-thymidine is added and plates are incubated an additional 36 hr priorto harvest using the manufacturer's protocol for SPA[³H] thymidineuptake assay system (Amersham Biosciences # RPNQ 0130). SPA-bead basedfluorescence is counted in a microbeta counter (Wallace Triplex 1450,Perkin Elmer).

Example 6 T Cell Proliferation Assay

A generalized procedure for a standard T cell proliferation assay thatcan be used to test compounds disclosed in this application is asfollows.

T cells are purified from spleens of 8-16 week old Balb/c mice using aPan T cell isolation kit (Miltenyi Biotech, Cat #130-090-861). Testcompounds are diluted in 0.25% DMSO and incubated with 2.5×10⁵ purifiedmouse splenic T cells in a final volume of 100 μl in flat clear bottomplates precoated for 90 min at 37° C. with 10 μg/ml each of anti-CD3 (BD#553057) and anti-CD28 (BD #553294) antibodies. Following 24 hrincubation, 1 μCi ³H-thymidine is added and plates incubated anadditional 36 hr prior to harvest using the manufacturer's protocol forSPA[³H] thymidine uptake assay system (Amersham Biosciences # RPNQ0130). SPA-bead based fluorescence was counted in a microbeta counter(Wallace Triplex 1450, Perkin Elmer).

Example 7 CD69 Inhibition Assay

A generalized procedure for a standard assay for the inhibition of Bcell activity that can be used to test compounds disclosed in thisapplication is as follows.

Total mouse splenocytes are purified from spleens of 8-16 week oldBalb/c mice by red blood cell lysis (BD Pharmingen #555899). Testingcompounds are diluted to 0.5% DMSO and incubated with 1.25×10⁶splenocytes in a final volume of 200 μl in flat clear bottom plates(Falcon 353072) for 60 min at 37° C. Cells are then stimulated with theaddition of 15 μg/ml IgM (Jackson ImmunoResearch 115-006-020), andincubated for 16 hr at 37° C., 5% CO₂. Following the 16 hr incubation,cells are transferred to conical bottom clear 96-well plates andpelleted by centrifugation at 1200×g×5 min. Cells are preblocked byCD16/CD32 (BD Pharmingen #553142), followed by triple staining withCD19-FITC (BD Pharmingen #553785), CD69-PE (BD Pharmingen #553237), and7AAD (BD Pharmingen #51-68981E). Cells are sorted on a BD FACSCaliburand gated on the CD19⁺/7AAD⁻ population. The levels of CD69 surfaceexpression on the gated population is measured versus test compoundconcentration.

Example 8 BMMC Degranulation

A generalized procedure for a standard assay for bone-marrow derivedmouse mast cell (BMMC) degranulation that can be used to test compoundsdisclosed in this application is as follows.

Bone-marrow derived mast cells were cultured for >4 weeks with IL-3 (10ng/ml) and SCF (10 ng/ml). The cells were determined to be >90%cKit⁺/FceRI⁺ by FACS analysis at the time of use. Cells (6×10⁷ cells/50ml) were serum-starved in a T150 tissue culture flask for 16 h in theabsence of IL-3 and SCF containing IgEα-DNP at 1 ug/ml. Overnightsensitized cells are washed twice in Tyrodes buffer and resuspended to5×10⁶ cells/ml. 5×10⁵ cells (100 ul) are plated in a 96 well microtiterplate (Falcon 353072) and test compounds are serially diluted to a finalconcentration 0.25% DMSO in the plate for 1 hr at 37° C., 5% CO₂. Wellsare treated with a DNP-BSA antigen challenge (50 ng/ml) and incubatedfor and additional 30 min at 37° C. Supernatants are assayed forhexosamimidase release versus control wells. Cell pellets aresimultaneously lysed and assed for total hexosamimidase release tocalculate specific release. Dose-response curves are generated using4-parameter logistical fit and IC50s calculated.

Example 9 Passive Cutaneous Anaphylaxis (PCA)

The following is a procedure for a standard PCA model used for measuringin vivo IgE anti-DNP Ab sensitization and DNP-BSA antigen for triggeringmast cell degranulation and release of immune regulators that causeacute vessel permeability monitored by Evan's blue dye into the inflamedarea in the mouse ear.

Reagents: Anti-DNP IgE: is supplied as 1.2 mg/ml in a phosphate bufferedsolution with BSA for additional protein and azide for sterility. Thisis diluted 1:100 in sterile PBS as a 12 ug/ml working stock that can befurther diluted in PBS to the appropriate concentration for injection. Afurther 1:5 dilution give a final 1:500 solution at 2.4 ng/ul. (10ul/ear=24 ng). Sterile PBS alone will be used as a negative control.-DNP-BSA: will be made up at 4 mg/ml in sterile ddH₂O and stored at 40°C. solution. It is further diluted 1:1 with sterile saline prior to use.This solution or a further dilution in saline is diluted 1:1 with 2%Evan's Blue in sterile saline that has been filtered though 0.02 umfilter and refiltered prior to injection. For these experiments a finalsolution of 0.5 mg/ml of DNP-BSA in 1% Evans blue can be used. Tail veininjections will be held constant at 200 ul=100 ug in 1% Evan's Blue.-Evan's blue dye: A 2% stock in saline will be sterile filtered anddiluted 1:1 with DNP-BSA saline solution for final concentration of 1%for injection.

General PCA Protocol Using Intradermal Ear Sensitization

1) On d0, animals, anesthetized with isofluorine, are passivelysensitized by intradermal injections of IgE anti-DNP using a 29-gaugeinsulin syringe. By convention, the right ear receives 10 ul intradermalinjection of anti-DNP IgE while the left ear receives PBS. 2) 20 hr postsensitization, antigen challenge is administered by tail i.v. injectionof DNP-BSA in 200 ul of 1% Evan's blue dye solution in saline. Tails areimmersed in warm water prior to iv injection to improve success. 3) 30minutes to 2 hr prior to this antigen challenge, drug is delivered sc orpo in 10% EtOH/20% cremaphor/70% saline. 4) Animals are sacrifice by CO₂inhalation 30-60 min post antigen challenge and ears are removed forextraction of Evan's blue dye in 500 ul of formamide overnight at 65° C.5) Blood is obtained by cardiac puncture just prior to final cervicaldislocation and processed for plasma to provide PK analysis. 6) Evan'sblue dye is quantified by reading absorbency of 200 ul of extractedsolution in microtiter plates at 620 nm.

Study Design of Experiment

Each animal has one anti-DNP IgE sensitized ear (right ear byconvention) and one PBS control ear (left ear by convention). Groups1-8: represent the vehicle and compound testing arms; Group 9:represents the non-antigen negative control; Group 10: represents thenon-sensitized challenged negative control; Group 11: represents thenon-antigen challenged, non-sensitized negative control group (Groups9-11 represent negative controls for background levels only and requireonly minimal number of animals per group.)

The compounds disclosed in the examples above were tested in the Sykbiochemical assay described herein (Example 3) and certain of thosecompounds exhibited an IC₅₀ value less than or equal to 1 micromolar.Certain of those compounds exhibited an IC₅₀ value less than or equal to100 nM. Certain of those compounds exhibited an IC₅₀ value less than orequal to 10 nM. Certain of those compounds exhibited an IC₅₀ value lessthan or equal to 1 nM.

Some of the compounds disclosed in Example 2 were tested in the B-cellproliferation assay (as described in Example 5) and exhibited an IC₅₀value less than or equal to 10 micromolar. Certain of those compoundsexhibited an IC₅₀ value less than or equal to 1 micromolar.

Certain of those compounds did not inhibit T-cell proliferation and hadIC₅₀ values greater than or equal to 5 micromolar when assayed underconditions described herein (as described in Example 6).

Certain compounds described herein exhibited IC₅₀ values for inhibitionof T-cell proliferation that were at least 3-fold, and in some instances5-fold, greater than the IC₅₀ values of those compounds for inhibitionof B-cell proliferation.

Some of the compounds described herein were tested in an assay forinhibition of B cell activity (under the conditions described in example7), and exhibited an IC₅₀ value less than or equal to 10 micromolar.Certain of those compounds exhibited an IC₅₀ value less than or equal to1 micromolar.

Some of the compounds disclosed in described herein exhibited bothbiochemical and cell-based activity. For example, some of the compoundsdescribed herein exhibited an IC₅₀ value less than or equal to 10micromolar in the Syk biochemical assay described herein (Example 3) andan IC₅₀ value less than or equal to 10 micromolar in at least one of thecell-based assays (other than the T-cell assay) described herein(Examples 4, 5, 7 or 8). Certain of those compounds exhibited an IC₅₀value less than or equal to 1 micromolar in the Syk biochemical assaydescribed herein (Example 4) and an IC₅₀ value less than or equal to 10micromolar in at least one of the cell-based assays (other than theT-cell assay) described herein (Examples 4, 5, 7 or 8). Certain of thosecompounds exhibited an IC₅₀ value less than or equal to 0.1 micromolarand an IC₅₀ value less than or equal to 10 micromolar in at least one ofthe cell-based assays (other than the T-cell assay) described herein(Examples 4, 5, 7 or 8).

While some embodiments have been shown and described, variousmodifications and substitutions may be made thereto without departingfrom the spirit and scope of the invention. For example, for claimconstruction purposes, it is not intended that the claims set forthhereinafter be construed in any way narrower than the literal languagethereof, and it is thus not intended that exemplary embodiments from thespecification be read into the claims. Accordingly, it is to beunderstood that the present invention has been described by way ofillustration and not limitations on the scope of the claims.

1. At least one chemical entity chosen from compounds of Formula I:

and pharmaceutically acceptable salts thereof, wherein R₁ is pyridinyl,pyridazinyl, or pyrazolyl, each of which is optionally substituted, orR₁ is

wherein A is an optionally substituted heteroaryl group having from 5 to7 ring atoms including the atoms shared with the 6 membered aromaticring; R₂ is chosen from substituted aryl and optionally substitutedheteroaryl; R₃ is hydrogen; R₄ is hydrogen; and R₅ is hydrogen, providedthat if R₁ is 2-methoxy-pyridin-5-yl, then R₂ is not 2,6-dimethylphenyl,2-methoxyphenyl, 2-chlorophenyl, or 2-fluorophenyl; if R₁ is indol-5-yl,then R₂ is not 2-chlorophenyl, furan-2-yl, or 3-chloro-4-fluorophenyl;if R₁ is 1H-indazol-5-yl, 1H-indol-6-yl, benzo[d]oxazole-6-yl,benzo[d]isoxazole-6-yl, benzothiazol-6-yl, or 3H-benzoimidazol-5-yl,then R₂ is not 3-aminophenyl; and if R₁ is 1H-indazol-6-yl, then R₂ isnot 3-carboxyphenyl or 4-carboxyphenyl.
 2. At least one chemical entityof claim 1, wherein R₁ is pyridinyl substituted with one or more groupschosen from hydroxy; —NR^(b)R^(c) wherein R^(b) is chosen from hydrogenand C₁-C₆ alkyl optionally substituted with one or two groups chosenfrom hydroxy and —OC₁-C₄ alkyl and R^(c) is independently chosen fromhydrogen and C₁-C₄ alkyl optionally substituted with one or two groupschosen from hydroxy and —OC₁-C₄ alkyl; heterocycloalkyl optionallysubstituted with one or two groups chosen from hydroxy, C₃-C₆cycloalkyl, C₁-C₄ alkyl, —C₁-C₄ alkyl-OH, —C₁-C₄ alkyl-O—C₁-C₄ alkyl,alkyl-NH₂, —N(C₁-C₄ alkyl)(C₁-C₄ alkyl), —NH(C₁-C₄ alkyl), and —OC₁-C₄alkyl; —OC₁-C₆ alkyl optionally substituted with one or two groupschosen from hydroxy, C₃-C₆ cycloalkyl, C₁-C₄ alkyl, —C₁-C₄ alkyl-OH,—C₁-C₄ alkyl-O—C₁-C₄ alkyl, —C₁-C₄ alkyl-NH₂, —N(C₁-C₄ alkyl)(C₁-C₄alkyl), —NH(C₁-C₄ alkyl), and —OC₁-C₄ alkyl; C₁-C₆ alkyl optionallysubstituted with one or two groups chosen from hydroxy, C₃-C₆cycloalkyl, C₁-C₄ alkyl, —C₁-C₄ alkyl-OH, —C₁-C₄ alkyl-O—C₁-C₄ alkyl,—C₁-C₄ alkyl-NH₂, —N(C₁-C₄ alkyl)(C₁-C₄ alkyl), —NH(C₁-C₄ alkyl), and—OC₁-C₄ alkyl; and pyrazolyl optionally substituted with one or twogroups chosen from hydroxy, C₃-C₆ cycloalkyl, C₁-C₄ alkyl, —C₁-C₄alkyl-OH, —C₁-C₄ alkyl-O—C₁-C₄ alkyl, —C₁-C₄ alkyl-NH₂, —N(C₁-C₄alkyl)(C₁-C₄ alkyl), —NH(C₁-C₄ alkyl), and —OC₁-C₄ alkyl.
 3. At leastone chemical entity of claim 2, wherein R₁ is pyridinyl substituted withone or more groups chosen from: hydroxy; —NR^(b)R^(c) wherein R^(b) ischosen from hydrogen and C₁-C₆ alkyl optionally substituted with one ortwo groups chosen from hydroxy and —OC₁-C₄ alkyl and R^(c) isindependently chosen from hydrogen and C₁-C₄ alkyl optionallysubstituted with one or two groups chosen from hydroxy and —OC₁-C₄alkyl; heterocycloalkyl optionally substituted with one or two groupschosen from hydroxy, —OC₁-C₄ alkyl, and C₁-C₄ alkyl; —OC₁-C₆ alkyloptionally substituted with one or two groups chosen from hydroxy,—OC₁-C₄ alkyl, —NH₂, —N(C₁-C₄ alkyl)H, and —N(C₁-C₄ alkyl)(C₁-C₄ alkyl);and C₁-C₆ alkyl optionally substituted with hydroxy.
 4. At least onechemical entity of claim 3, wherein R₁ is chosen from(2-methyl-2-hydroxypropoxy)pyridin-6-yl, (2-methoxyethoxy)pyridinyl,2-(dimethylamino)ethoxy-3-pyridinyl, hydroxyethoxy-5-pyridinyl,(3-methyl-3-hydroxyazetidine)pyridin-3-yl,(3-methyl-3-hydroxyazetidine)pyridin-2-yl,(3-hydroxyazetidine)pyridin-2-yl, (hydroxy(dimethylethyl))-5-pyridinyl,(4-methyl-4-hydroxypiperidine)pyridin-2-yl,(3-methyl-3-hydroxypiperidine)pyridin-2-yl, 5-morpholinopyridin-2-yl,6-morpholinopyridin-3-yl, ((2-methoxyethyl)(methyl)amino)pyridin-5-yl,((2-hydroxyethyl)(methyl)amino)pyridin-5-yl, 2-methoxy-4-pyridinyl, and2-hydroxy-5-pyridinyl.
 5. At least one chemical entity of claim 1,wherein R₁ is pyrazolyl substituted with one or two groups chosen fromcycloalkyl, C₁-C₆ alkyl, and C₁-C₆ alkyl substituted with one or moregroups chosen from hydroxy and —OC₁-C₄ alkyl.
 6. At least one chemicalentity of claim 5, wherein R₁ is chosen from(2-hydroxyethyl)-1H-pyrazol-4-yl, (2-hydroxypropyl)-1H-pyrazol-4-yl,(2-methoxyethyl)-1H-pyrazol-4-yl, 1-ethyl-1H-pyrazol-4-yl,1-isopropyl-1H-pyrazol-4-yl, 3-cyclopropyl-1H-pyrazol-5-yl, and1-ethyl-5-methyl-1H-pyrazol-3-yl.
 7. At least one chemical entity ofclaim 1, wherein R₁ is


8. At least one chemical entity of claim 7, wherein A is a pyrazolyl,oxazolyl, pyrrolyl, thiazolyl, or imidazolyl group, each of which isoptionally substituted.
 9. At least one chemical entity of claim 8,wherein the imidazolyl group is substituted with C₁-C₆ alkyl.
 10. Atleast one chemical entity of claim 7, wherein R₁ is chosen from1H-benzo[d]imidazol-6-yl, 1H-benzo[d]imidazol-5-yl, 1H-indazol-6-yl,1H-indazol-5-yl, 1-methyl-1H-benzo[d]imidazol-6-yl, benzoxazol-6-yl,benzoxazol-5-yl, imidazo[1,2-a]pyridine-6-yl, 1H-indole-6-yl,1H-indole-5-yl, benzothiazol-6-yl, and benzothiazol-5-yl.
 11. At leastone chemical entity of claim 1, wherein R₂ is chosen from optionallysubstituted heteroaryl, dihydroindolyl optionally substitued with oxoand C₁-C₆ alkyl, and dihydrobenzoxazinyl optionally substituted withoxo.
 12. At least one chemical entity of claim 11, wherein R₂ is chosenfrom 2,3-dimethyl-2H-indazol-6-yl, 1H-indazolyl-6-yl,1-methyl-1H-indazol-5-yl, 1-methyl-1H-indazol-6-yl,3,4-dihydro-2H-1,4-benzoxazin-3-one-6-yl, 1,3-benzoxazol-6-yl,3-aminoquinolin-6-yl, 2,3-dihydro-1H-indol-6-yl,1H,2H,3H-pyrido[2,3-b][1,4]oxazin-2-one, benzothiazolyl,2-aminoquinazolin-6-yl, 3,3-dimethylindolin-2-one,2,3-dihydro-1H-indol-2-one, 4-fluoro-1H-indazol-6-yl,5-fluoro-1H-indazol-6-yl, and 3-amino-1H-indazol-6-yl.
 13. At least onechemical entity of claim 11, wherein R₂ is chosen from1H-indazolyl-6-yl, 1-methyl-1H-indazol-5-yl, 1-methyl-1H-indazol-6-yl,3,4-dihydro-2H-1,4-benzoxazin-3-one-6-yl, 1,3-benzoxazol-6-yl,3-aminoquinolin-6-yl, and 2,3-dihydro-1H-indol-2-one-6-yl.
 14. At leastone chemical entity according to claim 1, wherein the compound ofFormula I is chosen from:N-[6-(1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]-1H-1,3-benzodiazol-6-amine;N-[6-(1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]-1H-indazol-6-amine;N-[6-(1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]-1-methyl-1H-1,3-benzodiazol-6-amine;N-[6-(1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]-1,3-benzoxazol-6-amine;N-[6-(1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]-1,3-benzoxazol-5-amine;5-{[6-(1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]amino}pyridin-2-ol;N-{imidazo[1,2-a]pyridin-6-yl}-6-(1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-amine;N-[6-(1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]-1H-indazol-5-amine;N-[6-(1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]-1H-indol-6-amine;N-[6-(1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]-1H-indol-5-amine;N-[6-(1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]-1,3-benzothiazol-6-amine;N-[6-(1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]-1,3-benzothiazol-5-amine;N-[6-(1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]-2-methoxypyridin-4-amine;6-[8-(1H-1,3-benzodiazol-5-ylamino)imidazo[1,2-a]pyrazin-6-yl]-3,4-dihydro-2H-1,4-benzoxazin-3-one;2-(4-{[6-(1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]amino}-1H-pyrazol-1-yl)ethan-1-ol;3-(4-{[6-(1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]amino}-1H-pyrazol-1-yl)propan-1-ol;N-[6-(1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]-1-(2-methoxyethyl)-1H-pyrazol-4-amine;1-ethyl-N-[6-(1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]-1H-pyrazol-4-amine;N-[6-(1,3-benzoxazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]-1H-1,3-benzodiazol-6-amine;N-[6-(1H-1,3-benzodiazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]-1H-indazol-6-amine;N-[6-(1-methyl-1H-indazol-5-yl)imidazo[1,2-a]pyrazin-8-yl]-1H-indazol-5-amine;N-[6-(3,4-dihydro-2H-1,4-benzoxazin-6-yl)imidazo[1,2-a]pyrazin-8-yl]-1H-indazol-6-amine;N-[6-(3-aminoquinolin-6-yl)imidazo[1,2-a]pyrazin-8-yl]-1,3-benzothiazol-5-amine;6-{8-[(2-methoxypyridin-4-yl)amino]imidazo[1,2-a]pyrazin-6-yl}-3,4-dihydro-2H-1,4-benzoxazin-3-one;N-[6-(2,3-dihydro-1H-indol-6-yl)imidazo[1,2-a]pyrazin-8-yl]-2-methoxypyridin-4-amine;N-[6-(1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]-1-(propan-2-yl)-1H-pyrazol-4-amine;1-methyl-N-[6-(1-methyl-1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]-1H-1,3-benzodiazol-6-amine,3-cyclopropyl-N-[6-(1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]-1H-pyrazol-5-amine;N-[6-(1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]-6-(morpholin-4-yl)pyridin-3-amine;N-[6-(2,3-dimethyl-2H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]-6-(morpholin-4-yl)pyridin-3-amine;5-N-[6-(1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]-2-N-(2-methoxyethyl)-2-N-methylpyridine-2,5-diamine;2-[(5-{[6-(1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]amino}pyridin-2-yl)(methyl)amino]ethan-1-ol;1-[(6-{[6-(1H-indazol-6-yl)imidazo[1,2-a]pyridin-8-yl]amino}pyridin-3-yl)oxy]-2-methylpropan-2-ol;7-(8-{[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]amino}imidazo[1,2-a]pyrazin-6-yl)-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-2-one;2-(4-{[6-(3,4-dihydro-2H-1,4-benzoxazin-7-yl)imidazo[1,2-a]pyrazin-8-yl]amino}-1H-pyrazol-1-yl)ethan-1-ol;6-(8-{[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]amino}imidazo[1,2-a]pyrazin-6-yl)-3,4-dihydro-2H-1,4-benzoxazin-3-one;2-(4-{[6-(1,3-benzothiazol-5-yl)imidazo[1,2-a]pyrazin-8-yl]amino}-1H-pyrazol-1-yl)ethan-1-ol;N-[6-(1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]-6-(2-methoxyethoxy)pyridin-3-amine;6-(8-{[6-(morpholin-4-yl)pyridin-3-yl]amino}imidazo[1,2-a]pyrazin-6-yl)quinazolin-2-amine;2-(4-{[6-(3,4-dihydro-2H-1,4-benzoxazin-6-yl)imidazo[1,2-a]pyrazin-8-yl]amino}-1H-pyrazol-1-yl)ethan-1-ol;6-[2-(dimethylamino)ethoxy]-N-[6-(1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]pyridin-3-amine;1-(6-{[6-(1H-indazol-6-yl)imidazo[1,2-a]pyridin-8-yl]amino}pyridin-3-yl)-3-methylazetidin-3-ol;2-[(5-{[6-(1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]amino}pyridin-2-yl)oxy]ethan-1-ol;3,3-dimethyl-6-(8-{[6-(morpholin-4-yl)pyridin-3-yl]amino}imidazo[1,2-a]pyrazin-6-yl)-2,3-dihydro-1H-indol-2-one;1-(5-{[6-(1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]amino}pyridin-2-yl)-3-methylazetidin-3-ol;1-(6-{[6-(1H-indazol-6-yl)imidazo[1,2-a]pyridin-8-yl]amino}pyridin-3-yl)azetidin-3-ol;2-(5-{[6-(1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]amino}pyridin-2-yl)-2-methylpropan-1-ol;1-[(5-{[6-(1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]amino}pyridin-2-yl)oxy]-2-methylpropan-2-ol;N-[5-(3,4-dihydro-2H-1,4-benzoxazin-6-yl)pyrazolo[1,5-a]pyrimidin-7-yl]-5-(morpholin-4-yl)pyridin-2-amine;N-[5-(1-methyl-1H-1,3-benzodiazol-6-yl)pyrazolo[1,5-a]pyrimidin-7-yl]-5-(morpholin-4-yl)pyridin-2-amine;6-(7-{[5-(morpholin-4-yl)pyridin-2-yl]amino}pyrazolo[1,5-a]pyrimidin-5-yl)-2,3-dihydro-1H-indol-2-one;N-[6-(3,4-dihydro-2H-1,4-benzoxazin-6-yl)imidazo[1,2-a]pyrazin-8-yl]-6-(morpholin-4-yl)pyridin-3-amine;N-[6-(3,4-dihydro-2H-1,4-benzoxazin-7-yl)imidazo[1,2-a]pyrazin-8-yl]-6-(morpholin-4-yl)pyridin-3-amine;2-[(6-{[5-(1H-indazol-6-yl)pyrazolo[1,5-a]pyrimidin-7-yl]amino}pyridin-3-yl)(methyl)amino]ethan-1-ol;6-(7-{[5-(morpholin-4-yl)pyridin-2-yl]amino}pyrazolo[1,5-a]pyrimidin-5-yl)-3,4-dihydro-2H-1,4-benzoxazin-3-one;N-[5-(1H-indol-6-yl)pyrazolo[1,5-a]pyrimidin-7-yl]-5-(morpholin-4-yl)pyridin-2-amine;6-(8-{[6-(morpholin-4-yl)pyridin-3-yl]amino}imidazo[1,2-a]pyrazin-6-yl)-2,3-dihydro-1H-indol-2-one,N-[6-(1-methyl-1H-1,3-benzodiazol-5-yl)imidazo[1,2-a]pyrazin-8-yl]-6-(morpholin-4-yl)pyridin-3-amine;2-[(5-{[6-(3,4-dihydro-2H-1,4-benzoxazin-7-yl)imidazo[1,2-a]pyrazin-8-yl]amino}pyridin-2-yl)(methyl)amino]ethan-1-ol;N-[6-(1-methyl-1H-1,3-benzodiazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]-6-(morpholin-4-yl)pyridin-3-amine;1-(5-{[6-(3,4-dihydro-2H-1,4-benzoxazin-6-yl)imidazo[1,2-a]pyrazin-8-yl]amino}pyridin-2-yl)-4-methylpiperidin-4-ol;N-[6-(1H-1,3-benzodiazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]-6-(morpholin-4-yl)pyridin-3-amine;1-(5-{[6-(3,4-dihydro-2H-1,4-benzoxazin-6-yl)imidazo[1,2-a]pyrazin-8-yl]amino}pyridin-2-yl)azetidin-3-ol,N-[5-(1H-1,3-benzodiazol-6-yl)pyrazolo[1,5-a]pyrimidin-7-yl]-5-(morpholin-4-yl)pyridin-2-amine;1-(5-{[6-(1H-indol-6-yl)imidazo[1,2-a]pyrazin-8-yl]amino}pyridin-2-yl-4-methylpiperidin-4-ol;N-[6-(1H-indol-6-yl)imidazo[1,2-a]pyrazin-8-yl]-6-(morpholin-4-yl)pyridin-3-amine;6-(8-{[6-(morpholin-4-yl)pyridin-3-yl]amino}imidazo[1,2-a]pyrazin-6-yl)-3,4-dihydro-2H-1,4-benzoxazin-3-one,1-ethyl-N-[6-(1H-indazol-6-yl)imidazo[1,2-a]pyridin-8-yl]-5-methyl-1H-pyrazol-3-amine;6-[8-({6-[(2-hydroxyethyl)(methyl)amino]pyridin-3-yl}amino)imidazo[1,2-a]pyrazin-6-yl]-3,4-dihydro-2H-1,4-benzoxazin-3-one;1-(5-{[6-(1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]amino}pyridin-2-yl)-3-methylpiperidin-3-ol;N-[6-(1H-indazol-6-yl)imidazo[1,2-a]pyridin-8-yl]-6-(morpholin-4-yl)pyridazin-3-amine;7-(8-{[6-(morpholin-4-yl)pyridin-3-yl]amino}imidazo[1,2-a]pyrazin-6-yl)-1H,2H,3H-pyrido[2,3b][1,4]oxazin-2-one;N-[6-(1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]-6-[4-(propan-2-yl)piperazin-1-yl]pyridin-3-amine;N-[6-(4-fluoro-1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]-6-(morpholin-4-yl)pyridin-3-amine;2-N-[6-(1H-indazol-6-yl)imidazo[1,2-a]pyridin-8-yl]-5-N-(2-methoxyethyl)-5-N-methylpyridine-2,5-diamine;6-(1H-benzo[d]imidazol-6-yl)-N-(5-morpholinopyridin-2-yl)imidazo[1,2-b]pyridazin-8-amine;6-(3-amino-1H-indazol-6-yl)-N-(5-morpholinopyridin-2-yl)imidazo[1,2-b]pyridazin-8-amine;2-[(6-{[6-(1H-indazol-6-yl)imidazo[1,2-a]pyridin-8-yl]amino}pyridin-3-yl)(methyl)amino]ethan-1-ol;1-(5-{[6-(1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]amino}pyridin-2-yl-4-methylpiperidin-4-ol;1-(5-{[6-(1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]amino}pyridin-2-yl)azetidin-3-ol;6-(1H-indol-6-yl)-N-(5-morpholinopyridin-2-yl)imidazo[1,2-b]pyridazin-8-amine;N-[6-(5-fluoro-1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]-6-(morpholin-4-yl)pyridin-3-amine,(3S)-1-(5-{[6-(1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]amino}pyridin-2-yl)-3-methylpiperidin-3-ol,(3R)-1-(5-{[6-(1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]amino}pyridin-2-yl-3-methylpiperidin-3-ol,1-(5-{[6-(1H-indol-6-yl)imidazo[1,2-a]pyrazin-8-yl]amino}pyridin-2-yl)-3-methylazetidin-3-ol,[(2R)-4-(5-{[6-(1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]amino}pyridin-2-yl)morpholin-2-yl]methanol,[(2S)-4-(5-{[6-(1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]amino}pyridin-2-yl)morpholin-2-yl]methanol,N-[6-(1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]-2-(morpholin-4-yl)pyrimidin-5-amine,1-ethyl-N-(6-{1H-pyrrolo[3,2-b]pyridin-6-yl}imidazo[1,2-a]pyrazin-8-yl)-1H-pyrazol-4-amine,and2-{4-[(6-{1H-pyrrolo[3,2-b]pyridin-6-yl}imidazo[1,2-a]pyrazin-8-yl)amino]-1H-pyrazol-1-yl}ethan-1-ol.15. A pharmaceutical composition comprising at least one chemical entityof claim 1, together with at least one pharmaceutically acceptablevehicle chosen from carriers, adjuvants, and excipients.
 16. A methodfor treating a patient having a disease responsive to the inhibition ofSyk activity, comprising administering to the patient an effectiveamount of at least one chemical entity according to claim
 1. 17. Themethod according to claim 16, wherein the patient is a human.
 18. Themethod according to claim 16, wherein an effective amount of said atleast one chemical entity is administered by a method chosen fromintravenously, intramuscularly, and parenterally.
 19. The methodaccording to claim 16, wherein an effective amount of said at least onechemical entity is administered orally.
 20. The method according toclaim 16, wherein the disease responsive to inhibition of Syk activityis cancer.
 21. The method according to claim 20, wherein the diseaseresponsive to inhibition of Syk activity is B-cell lymphoma andleukemia.
 22. The method according to claim 16, wherein the diseaseresponsive to inhibition of Syk activity is rheumatoid arthritis. 23.The method according to claim 16, wherein the disease responsive toinhibition of Syk activity is allergic rhinitis.
 24. The methodaccording to claim 16, wherein the disease responsive to inhibition ofSyk activity is chronic obstructive pulmonary disease (COPD).
 25. Themethod according to claim 16, wherein the disease responsive toinhibition of Syk activity is adult respiratory distress syndrome(ARDs).
 26. The method according to claim 16, wherein the diseaseresponsive to inhibition of Syk activity is an allergy-inducedinflammatory disease.
 27. The method according to claim 16, wherein thedisease responsive to inhibition of Syk activity is multiple sclerosis.28. The method according to claim 16, wherein the disease responsive toinhibition of Syk activity is autoimmune disease.
 29. The methodaccording to claim 16, wherein the disease responsive to inhibition ofSyk activity is inflammatory disease.
 30. The method according to claim16, wherein the disease responsive to inhibition of Syk activity isacute inflammatory reaction.
 31. The method according to claim 16,wherein the disease responsive to inhibition of Syk activity is allergicdisorder.
 32. The method according to claim 16, wherein the diseaseresponsive to inhibition of Syk activity is polycystic kidney disease.33. A method for determining the presence of Syk in a sample, comprisingcontacting the sample with at least one chemical entity of claim 1 underconditions that permit detection of Syk activity, detecting a level ofSyk activity in the sample, and therefrom determining the presence orabsence of Syk in the sample.
 34. A method for inhibiting B-cellactivity comprising contacting cells expressing Syk with at least onechemical entity of claim 1, in an amount sufficient to detectablydecrease B-cell activity in vitro.
 35. A method for inhibiting ATPhydrolysis, the method comprising contacting cells expressing Syk withat least one chemical entity of claim 1 in an amount sufficient todetectably decrease the level of ATP hydrolysis in vitro.